KR101933844B1 - Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection - Google Patents
Novel 6-fused heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection Download PDFInfo
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Abstract
본 발명은 하기 화학식 I의 신규한 화합물, 상기 화합물을 포함하는 조성물 및 상기 화합물의 사용 방법을 제공한다. 이러한 화합물은 인간에서 치료 및/또는 예방에 유용하고, 특히 HBV 감염의 치료를 위한 HBV 캡시드를 표적하는 B형 간염 바이러스(HBV) 억제제이다:
[화학식 I]
상기 식에서,
R1, R2, R3, R4, R5, R6, X, Y, W 및 n은 본원에 기재된 바와 같다.The present invention provides novel compounds of formula (I), compositions comprising such compounds and methods of use of said compounds. Such compounds are useful in therapy and / or prevention in humans, and in particular are hepatitis B virus (HBV) inhibitors which target HBV capsids for the treatment of HBV infection:
(I)
In this formula,
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, W and n are as described herein.
Description
본 발명은 인간에서 치료 및/또는 예방에 유용한 유기 화합물, 특히 HBV 감염의 치료를 위해 HBV 캡시드를 표적하는 B형 간염 바이러스(HBV) 억제제에 관한 것이다.The present invention relates to an HBV inhibitor which targets HBV capsids for the treatment of organic compounds useful in therapy and / or prevention in humans, especially HBV infections.
본 발명은 약학 활성을 갖는 신규한 6-융합된 헤테로아릴다이하이드로피리미딘, 이의 제조, 이를 함유하는 약학 조성물 및 약제로서 이의 가능한 용도에 관한 것이다.The present invention relates to novel 6-fused heteroaryl dihydropyrimidines having pharmacological activity, their preparation, pharmaceutical compositions containing them and their possible uses as medicaments.
본 발명은 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체에 관한 것이다:The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
[화학식 I](I)
상기 식에서,In this formula,
R1 내지 R6, X, Y, W 및 n은 하기 기재된 바와 같다.R 1 to R 6 , X, Y, W and n are as described below.
B형 간염 바이러스(HBV)는 헤파드나바이러스과 계열 바이러스의 종이다. HBV는 특히 아시아-태평양 지역에서 4억 명 이상의 사람들이 이 작은 외피 DNA 바이러스에 의해 만성적으로 감염된, 전세계 심각한 공중 보건 문제이다. 대부분의 사람이 급성 증상 후 감염이 해결되는 것처럼 보이지만, HBV 환자의 15 내지 40%는 이들의 수명 동안 임상 질환, 특히, 간염, 간경화증 및 간세포 암종으로 최종적으로 발달할 것이다. 매년 50만 내지 100만 명의 사람들이 HBV 감염에 의해 야기된 간 질환의 말기로 사망한다. Hepatitis B virus (HBV) is a species of hepadnavirus and family viruses. HBV is a serious public health problem worldwide, with more than 400 million people in the Asia-Pacific region being chronically infected by this small enveloped DNA virus. While most people appear to resolve the infection after acute symptoms, 15-40% of HBV patients will eventually develop clinical disease, especially hepatitis, liver cirrhosis and hepatocellular carcinoma during their lifetime. Every year, between 500,000 and 1 million people die from liver disease caused by HBV infection.
HBV 생명주기는 간세포의 표면에서 "데인(Dane)" 입자와 미확인된 수용체의 결합으로 시작한다. 진입 후, 바이러스 게놈은 핵으로 전달되고, 여기서 공유결합 폐환상 DNA(cccDNA)는 바이러스 이완형 환상 DNA의 DNA 수복을 통해 형성된다. 대부분의 다른 DNA 바이러스의 기작과는 달리, HBV cccDNA는 1.1-게놈 단위-길이 RNA 카피(전구게놈(pregenomic) RNA)의 역전사를 통해 복제된다. 바이러스 전구게놈 RNA는 다른 2개의 바이러스 구성성분, 즉, 캡시드 단백질 및 폴리머라아제, 뿐만 아니라 일부 숙주 인자와 상호작용하여 바이러스 DNA 복제가 발생하는 캡시드 입자를 형성한다. 이어서, 캡시드에 싸인 게놈의 대부분의 카피를 비리온 조립 및 분비를 위해 외피 단백질과 효율적으로 회합하고; 이러한 게놈의 소수를 핵으로 바꿔 넣고, 이들을 cccDNA로 전환한다. The HBV life cycle begins with the combination of "Dane" particles and unidentified receptors on the surface of the hepatocytes. After entry, the viral genome is transferred to the nucleus, where the covalently bound cystic DNA (cccDNA) is formed through DNA repair of the viral relaxed circular DNA. Unlike most other DNA virus mechanisms, HBV cccDNA is replicated through reverse transcription of a 1.1-genome unit-length RNA copy (pregenomic RNA). Viral precursor genomic RNA interacts with two other viral components, namely, capsid proteins and polymerases, as well as some host factors, to form capsid particles where viral DNA replication occurs. Subsequently, most copies of the genome encapsidated with capsids are efficiently associated with envelope proteins for virion assembly and secretion; Replace a few of these genomes with nuclei and convert them to cccDNA.
현재, 시중에는 다음 두 가지 유형의 항-HVB 약제가 존재한다: 바이러스 폴리머라아제를 표적하는 뉴클레오시드(뉴클레오티드) 유사체(라미부딘, 아데포비르, 테노포비르, 텔비부딘 및 엔테카비르) 및 숙주 면역 기능을 조절하는 인터페론. 라미부딘 및 아데포비르에 대한 내성을 부여하는 폴리머라아제의 1차 서열 중의 돌연변이는 임상으로 확인되었고 혈청 바이러스 역가 반등(라미부딘 요법을 시작하고 3년 이내에 치료받은 경험이 있는 환자의 70%)의 기저를 이룬다. 텔비부딘, 아데포비르 및 엔테카비르에 대한 내성은 더욱 드물게 발생하지만 기록되었다. 인터페론 알파는 B형 간염에 이용가능한 다른 주요한 요법이지만, 불량한 장기간 반응 및 쇄약 부작용으로 인해 제한되었다. 일부 바이러스 유전자형은 인터페론 요법에 대하여 우수한 반응을 보이지 않는다. 지금, HBV 감염의 표준 임상 치유법은 HBsAg의 손실 및/또는 혈청전환이다. 치료받은 환자의 대다수(약 90% 이상)는 이 목적을 달성하는 데 실패한다. 이 문제점은 주로 핵에서 스스로 복제할 수 없는 바이러스 cccDNA의 안정적인 풀(pool)의 존재에 기인하고, 따라서, 뉴클레오시드(뉴클레오티드) 유사체에 대한 접근성을 보이지 않는다. Currently, there are two types of anti-HBV agents in the market: nucleoside (nucleotide) analogues (lamivudine, adefovir, tenofovir, telbivudine and entecavir) targeting the viral polymerase, Interferon that regulates immune function. Mutations in the primary sequence of polymerases conferring resistance to lamivudine and adefovir have been clinically validated and have been shown to be associated with baseline serum viral titer rebound (70% of patients who have started lamivudine therapy and have been treated within 3 years) Respectively. Resistance to telbivudine, adefovir and entecavir occurred less frequently but was recorded. Interferon alpha is another major therapy available for hepatitis B, but is limited by poor long-term response and constipation adverse reactions. Some virus genotypes do not show a good response to interferon therapy. Now, standard clinical cure for HBV infection is loss of HBsAg and / or serum conversion. The majority of patients treated (more than 90%) fail to achieve this goal. This problem is mainly due to the presence of a stable pool of viral cccDNA that can not replicate in the nucleus itself and therefore does not show access to nucleoside (nucleotide) analogs.
이런 이유로, HBV 감염에 대한 치료의 개발에 있어서 개선된 특징을 갖는 치료 및 다양한 접근법에 대한 의학적 요구가 분명히 있다.For this reason, there is a clear medical need for therapies and diverse approaches with improved features in the development of therapies for HBV infection.
HBV 캡시드 단백질은 HBV 복제시 필수적인 역할을 한다. HBV는 캡시드(또는 코어) 단백질의 240개 카피를 포함하는 20면체 코어를 갖는다. 캡시드 단백질의 두드러진 생물학적 기능은 전구게놈 RNA를 캡시드로 싸기 위한 구조적 단백질로서 작용하고 세포질에서 미성숙 캡시드 입자를 형성하는 것이다. 이 단계는 바이러스 DNA 복제를 위한 전제 조건이다. HBV 캡시드는 세포질에 존재하는 코어 이량체의 많은 카피로부터 자발적으로 자가 조립한다. 삼량체 핵의 형성 및 후속 신장 반응은 첨가가 완료될 때까지 하나의 이량체 하위단위를 한번에 첨가함으로써 발생하는 것으로 입증되었다. 이 기능 이외에, 캡시드 단백질은 이의 C-말단 인산화 부위의 상이한 인산화 상태를 통해 바이러스 DNA 합성을 조절한다. 거의 전장 이완형 환상 DNA가 바이러스 전구게놈 RMA의 역-전사를 통해 형성될 때, 미성숙 캡시드는 성숙 캡시드가 된다. 한편으로는, 캡시드 단백질은 캡시드 단백질의 C-말단 영역의 아르기닌-풍부 도메인에 위치된 핵 국소화 신호에 의해 바이러스 이완형 환상 게놈의 핵 전좌를 촉진할 수 있다. 핵에서, 바이러스 cccDNA 꼬마염색체의 구성성분로서, 캡시드 단백질은 cccDNA 꼬마염색체의 작용기에서 구조적인 조절 역할을 할 수 있다. 캡시드 단백질은 또한 소포체에서 바이러스 큰 외피 단백질과 상호작용하고 간세포로부터 온전한 바이러스 입자의 방출을 촉발시킨다. HBV capsid proteins play an essential role in HBV replication. HBV has an icosahedral core that contains 240 copies of the capsid (or core) protein. The prominent biological function of the capsid protein is to act as a structural protein to encapsulate the precursor genomic RNA and form immature capsid particles in the cytoplasm. This step is a prerequisite for viral DNA replication. HBV capsids self-assemble spontaneously from many copies of core dimers present in the cytoplasm. The formation of trimer nuclei and subsequent elongation reactions have been demonstrated to occur by adding one dimeric subunit at a time until addition is complete. In addition to this function, the capsid protein regulates viral DNA synthesis through different phosphorylation states of its C-terminal phosphorylation site. When almost full-length relaxed circular DNA is formed through reverse-transcription of the virus precursor genome RMA, immature capsids become mature capsids. On the other hand, the capsid protein can promote nuclear translocation of the viral relaxation annular genome by a nuclear localization signal located in the arginine-rich domain of the C-terminal region of the capsid protein. In the nucleus, as a component of the viral cccDNA chromosome, the capsid protein can play a structural regulatory role in the functional group of the ccc DNA chromosome. The capsid protein also interacts with the viral envelope proteins in the endoplasmic reticulum and triggers the release of intact viral particles from the hepatocytes.
항-HBV 억제제와 관련된 한 쌍의 캡시드가 보고되었다. 예를 들면, AT-61 및 AT-130으로 명명된 화합물을 포함하는 페닐프로펜아미드 유도체(Feld J. et al., Antiviral Research 2007, 168-177), 및 발레안트 알앤디(Valeant R&D)(WO 2006/033995)로부터의 티아졸리딘-4-온의 부류가 pgRNA 패키징을 억제하는 것으로 나타났다. 최근 연구는 페닐프로펜아미드가 사실상 HBV 캡시드 조립의 촉진 인자이고, 이의 작용이 빈 캡시드의 형성을 초래함을 제시하였다. 이러한 매우 흥미로운 결과는 성공적인 바이러스 조립에 있어서 운동 경로의 중요성을 예증한다.A pair of capsids associated with anti-HBV inhibitors have been reported. For example, phenylpropenamide derivatives including compounds named AT-61 and AT-130 (Feld J. et al., Antiviral Research 2007 , 168-177), and Valeant R & D 2006/033995) disclose that a group of thiazolidin-4-ones lt; RTI ID = 0.0 > pgRNA < / RTI > Recent studies have suggested that phenylpropenamide is in fact a promoter of HBV capsid assembly, and that its action results in the formation of empty capsids. These very interesting results illustrate the importance of the motor pathway in successful viral assembly.
Bay 41-4109, Bay 38-7690 및 Bay 39-5493으로 명명된 화합물을 포함하는 헤테로아릴다이하이드로피리미딘 또는 HAP는 조직 배양 기반 스크리닝에서 발견되었다(문헌[Deres K. et al., Science 2003, 893]). 이러한 HAP 유사체는 합성 알로스테릭 활성인자로서 작용하고, 코어 단백질의 분해를 야기하는 이상한 캡시드 형성을 유도할 수 있다. 또한, HAP 유사체는 아마도 캡시드 '호흡' 동안 풀어진 이량체와 HAP의 상호작용에 의해, 코어 단백질을 예비조립된 캡시드로부터 비캡시드 중합체로 재조직하여 개별적인 하위단위간 결합을 일시적으로 차단한다. Bay 41-4109를 HBV 감염된 유전자 이식 마우스 또는 인간화된 마우스 모델에 투여하고 HBV DNA 감소와 함께 생체내 효능을 입증하였다(문헌[Deres K. et al., Science 2003, 893]; [Brezillon N. et al., PLoS ONE 2011, e25096]). 이는 또한 분자 '웨지(wedge)'로서 작용하고 정상 캡시드 단백질 기하학적 구조 및 캡시드 형성을 방해하는 소분자인 비스-ANS를 나타내었다(문헌[Zlotnick A. et al., J. Virol. 2002, 4848-4854]).Heteroaryl dihydropyrimidines or HAPs comprising compounds named Bay 41-4109, Bay 38-7690 and Bay 39-5493 were found in tissue culture based screening (Deres K. et al., Science 2003 , 893). Such HAP analogs can act as synthetic allosteric activators and induce the formation of strange capsids that cause degradation of the core protein. In addition, HAP analogs temporarily reorganize core proteins from pre-assembled capsids to non-capsid polymers by interfering with HAPs, perhaps solved during the capsid 'breathing' to temporarily block individual subunits binding. Bay 41-4109 was administered to HBV infected transgenic or humanized mouse models and demonstrated in vivo efficacy with HBV DNA reduction (Deres K. et al., Science 2003 , 893); [Brezillon N. et al., PLoS ONE 2011 , e25096). It also exhibited bis-AN, which acts as a molecular 'wedge' and is a small molecule that interferes with normal capsid protein geometry and capsid formation (Zlotnick A. et al., J. Virol. 2002 , 4848-4854 ]).
본 발명은 하기 화학식 I의 신규한 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체에 관한 것이다:The present invention relates to a novel compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
[화학식 I](I)
상기 식에서,In this formula,
R1은 수소, 할로겐 또는 C1-6알킬이고;R 1 is hydrogen, halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소, 하이드록시C1-6알킬, 아미노카본일, C1-6알콕시카본일 또는 카복시이고;R 5 is hydrogen, hydroxyC 1-6 alkyl, aminocarbonyl, C 1-6 alkoxycarbonyl or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X는 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y는 -CH2-, -O- 또는 -N(R7)-이되, R7은 수소, C1-6알킬, 할로C1-6알킬, C3-7사이클로알킬-CmH2m-, C1-6알콕시카본일-CmH2m-, -CtH2t-COOH, -할로C1-6알킬-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CtH2t-, 카복시스피로[3.3]헵틸, 카복시페닐-CmH2m- 또는 카복시피리딘일-CmH2m-이고;Y is -CH 2 -, -O- or -N (R 7) - provided that, R 7 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m - , -C 1-6 alkoxycarbonyl-C m H 2m- , -C t H 2t -COOH, -haloC 1-6 alkyl-COOH, - (C 1-6 alkoxy) C 1-6 alkyl-COOH, - C 1-6 alkyl, -OC 1-6 alkyl, -COOH, -C 3-7 cycloalkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, hydroxy -C t H 2t -, carboxy-spiro [3.3] heptyl, carboxyphenyl -C m H 2m - or carboxy pyridinyl -C m H 2m -, and;
W는 -CH2-, -C(C1-6알킬)2-, -O- 또는 카본일이고;W is -CH 2 -, -C (C 1-6 alkyl) 2 -, -O- or carbonyl;
n은 0 또는 1이고;n is 0 or 1;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다. t is from 1 to 7;
본 발명은 또한 상기 화합물의 제조, 본 발명에 따른 화합물에 기초한 약제 및 이의 생성뿐만 아니라 HBV 감염의 치료 또는 예방을 위한 본 발명의 화학식 I의 화합물 또는 다른 화합물의 용도에 관한 것이다.The invention also relates to the use of compounds of formula I or other compounds of the invention for the manufacture of said compounds, medicaments based on the compounds according to the invention and their production, as well as for the treatment or prevention of HBV infection.
도 1은 화합물 B1의 X-선 결정 구조를 도시한다.Figure 1 shows the X-ray crystal structure of compound B1.
정의Justice
본원에 사용된 용어 "C1-6알킬"은 1 내지 6개, 특히 1 내지 4개의 탄소 원자를 함유하는 포화된 직쇄 또는 분지쇄 알킬 기, 예를 들면, 메틸, 에틸, 프로필, 이소프로필, 1-부틸, 2-부틸, t-부틸 등을 의미한다. 특정한 "C1-6알킬" 기는 메틸, 에틸, 이소프로필 및 t-부틸이다.The term " C 1-6 alkyl " as used herein refers to saturated straight or branched chain alkyl groups containing from 1 to 6, especially 1 to 4 carbon atoms, such as methyl, ethyl, 1-butyl, 2-butyl, t- butyl and the like. Particular "C 1-6 alkyl" groups are methyl, ethyl, isopropyl, and t- butyl.
용어 "-CmH2m-"은 단독으로 또는 조합하여 m개(m≠0)의 탄소 원자 또는 결합(m=0)을 함유하는 포화된 직쇄 또는 분지쇄 알킬 기를 의미한다. 특히, "-CmH2m-"은 단독으로 또는 조합하여 1 내지 4개의 탄소 원자를 함유하는 포화된 직쇄 또는 분지쇄 알킬 기를 의미한다.The term " -C m H 2m - ", alone or in combination, signifies a saturated straight-chain or branched-chain alkyl group containing m (m ≠ 0) carbon atoms or bonds (m = 0). In particular, " -C m H 2m - ", alone or in combination, signifies a saturated straight-chain or branched-chain alkyl group containing from 1 to 4 carbon atoms.
용어 "-CtH2t-"는 단독으로 또는 조합하여 화학 연결 또는 (t≠0)개의 탄소 원자 또는 결합(t=0)을 함유하는 포화된 직쇄 또는 분지쇄 알킬 기를 의미한다. 특히, "-CtH2t-"는 단독으로 또는 조합하여 1 내지 4개의 탄소 원자를 함유하는 포화된 직쇄 또는 분지쇄 알킬 기를 의미한다.The term " -C t H 2t - ", alone or in combination, signifies a chemical bond or a saturated straight or branched chain alkyl group containing (t ≠ 0) carbon atoms or bonds (t = 0). In particular, " -C t H 2t - ", alone or in combination, signifies a saturated straight-chain or branched-chain alkyl group containing from 1 to 4 carbon atoms.
용어 "C1-6알콕시"는 단독으로 또는 조합하여 기 C1-6알킬-O-(여기서, "C1-6알킬"은 상기 정의된 바와 같다), 예를 들면, 메톡시, 에톡시, 프로폭시, 이소-프로폭시, n-부톡시, 이소-부톡시, 2-부톡시, t-부톡시 등을 의미한다. 특정한 "C1-6알콕시" 기는 메톡시 및 에톡시, 더욱 특히 메톡시이다.The term "C 1-6 alkoxy", alone or in combination, signifies a group C 1-6 alkyl-O- (where "C 1-6 alkyl" is defined above), for example methoxy, ethoxy Propoxy, iso-propoxy, n -butoxy, iso-butoxy, 2-butoxy, t -butoxy and the like. Particular "C 1-6 alkoxy" groups are methoxy and ethoxy, more particularly methoxy.
용어 "C3-7사이클로알킬"은 단독으로 또는 조합하여 3 내지 7개의 탄소 원자, 특히 3 내지 6개의 탄소 원자를 함유하는 포화된 탄소 고리, 예를 들면, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸 등을 지칭한다. 특정한 "C3-7사이클로알킬" 기는 사이클로프로필, 사이클로펜틸 및 사이클로헥실이다.The term " C 3-7 cycloalkyl ", alone or in combination, signifies a saturated carbon ring containing from 3 to 7 carbon atoms, especially 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, and the like. Particular "C 3-7 cycloalkyl" groups are cyclopropyl, cyclopentyl, and cyclohexyl.
용어 "카복시"는 기 -COOH를 지칭한다.The term " carboxy " refers to the group -COOH.
용어 "카본일"은 단독으로 또는 조합하여 기 -C(O)-를 지칭한다.The term " carbonyl ", alone or in combination, refers to the group -C (O) -.
용어 "설폰일"은 단독으로 또는 조합하여 기 -S(O)2-를 지칭한다.The term " sulfonyl ", alone or in combination, refers to the group -S (O) 2 -.
용어 "할로겐" 및 "할로"는 본원에서 상호교환적으로 사용되고, 플루오로, 클로로, 브로모 또는 요오도를 지칭한다. The terms " halogen " and " halo " are used interchangeably herein and refer to fluoro, chloro, bromo or iodo.
용어 "할로C1-6알킬"은 하나 이상의 수소 원자가 동일하거나 상이한 할로겐 원자, 특히 플루오로 원자로 대체된 알킬 기를 지칭한다. 할로C1-6알킬의 예는 모노플루오로-, 다이플루오로- 또는 트라이플루오로-메틸, -에틸 또는 -프로필, 예를 들면, 3,3,3-트라이플루오로프로필, 2-플루오로에틸, 2,2,2-트라이플루오로에틸, 플루오로메틸, 다이플루오로에틸 또는 트라이플루오로메틸을 포함한다. The term " haloC 1-6 alkyl " refers to an alkyl group in which one or more hydrogen atoms are replaced by the same or different halogen atoms, especially fluoro atoms. Examples of halo C 1-6 alkyl are monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoro Ethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoroethyl or trifluoromethyl.
용어 "C1-6알콕시카본일"은 기 C1-6알콕시-C(O)-(여기서, "C1-6알콕시"는 상기 정의된 바와 같다)를 지칭한다.The term "C 1-6 alkoxycarbonyl" refers to a group C 1-6 alkoxy-C (O) -, wherein "C 1-6 alkoxy" is as defined above.
용어 "카복시-CmH2m-"은 기 "-CmH2m-COOH"(여기서, "-CmH2m-"은 상기 정의된 바와 같다)를 지칭한다.The term "carboxy -C m H 2m -" is a group "-C m H 2m -COOH" - refers to a (here, "-C m H 2m" is as defined above).
용어 "C3-7사이클로알킬-CmH2m-"은 수소 원자 중 하나가 "-CmH2m-" 기로 대체된 상기 정의된 바와 같은 "C3-7사이클로알킬" 기를 지칭한다.The term "C 3-7 cycloalkyl-C m H 2m -" refers to a "C 3-7 cycloalkyl" group as defined above wherein one of the hydrogen atoms is replaced with a "-C m H 2m -" group.
용어 "거울상이성질체"는 서로의 비중첩가능한 거울상인 화합물의 2개 입체이성질체를 나타낸다.The term " enantiomers " refers to two stereoisomers of compounds that are non-overlapping enantiomers of one another.
용어 "부분입체이성질체"는 2개 이상의 키랄 중심을 갖고 분자가 서로의 거울상이 아닌 입체이성질체를 나타낸다. 부분입체이성질체는 상이한 물리적 특성, 예를 들면, 융점, 비점, 스펙트럼 특성 및 활성을 갖는다.The term " diastereomer " refers to stereoisomers having two or more chiral centers and wherein the molecules are not mirror images of each other. The diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics and activity.
본 발명에 따른 화합물은 이의 약학적으로 허용되는 염의 형태로 존재할 수 있다. 용어 "약학적으로 허용되는 염"은 본 발명의 화학식 I의 화합물 또는 다른 화합물의 생물학적 유효성 및 특성을 보유하고 적합한 무독성 유기 또는 무기 산, 또는 유기 또는 무기 염기로부터 형성되는 통상의 산-부가 염 또는 염기-부가 염을 지칭한다. 산-부가 염은 예를 들면, 무기 산, 예컨대 염산, 브롬화수소산, 요오드화수소산, 황산, 설팜산, 인산 및 질산으로부터 유도된 것, 및 유기 산, 예컨대 p-톨루엔설폰산, 살리실산, 메탄설폰산, 옥살산, 숙신산, 시트르산, 말산, 락트산, 푸마르산 등으로부터 유도된 것을 포함한다. 염기-부가 염은 암모늄, 칼륨, 나트륨, 및 4차 암모늄 하이드록사이드, 예컨대 테트라메틸 암모늄 하이드록사이드로부터 유도된 것을 포함한다. 약학 화합물을 염으로 화학 변형시키는 것은 화합물의 개선된 물리적 및 화학적 안정성, 흡습성, 유동성 및 용해도를 수득하기 위해 약학 화학자에게 널리 공지된 기법이다. 이는 예를 들면, 문헌[Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435]; 또는 [Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457]에 기재되어 있다. 특정한 것은 화학식 I의 화합물의 나트륨 염이다.The compounds according to the invention may exist in the form of their pharmaceutically acceptable salts. The term " pharmaceutically acceptable salts " refers to conventional acid-addition salts which possess the biological effectiveness and properties of the compounds of formula (I) or other compounds of the invention and are formed from suitable non-toxic organic or inorganic acids, Base-addition salts. Acid-addition salts include, for example, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and organic acids such as p- toluenesulfonic acid, salicylic acid, , Oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Base-addition salts include those derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical transformation of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of the compound. For example, in Bastin RJ, et al ., Organic Process Research & Development 2000, 4, 427-435; Or [Ansel, H., et al ., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Particular is the sodium salt of the compound of formula (I).
1개 또는 여러개의 키랄 중심을 함유하는 본 발명의 화학식 I의 화합물 또는 다른 화합물은 라세미체, 부분입체이성질체 혼합물, 또는 광학적으로 활성인 단일 이성질체로서 존재할 수 있다. 라세미체는 공지된 방법에 따라 거울상이성질체로 분리될 수 있다. 특히, 결정화에 의해 분리될 수 있는 부분입체이성질체 염은 라세미 혼합물을 광학적으로 활성인 산, 예컨대 D- 또는 L-타르타르산, 만델산, 말산, 락트산 또는 캄포르설폰산과 반응시켜 형성된다.The compounds of formula (I) or other compounds of the present invention containing one or more chiral centers may exist as racemates, diastereomeric mixtures, or as optically active single isomers. The racemate can be separated into the enantiomers according to known methods. In particular, diastereoisomeric salts that can be separated by crystallization are formed by reacting a racemic mixture with an optically active acid such as D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
HBV 캡시드 억제제HBV capsid inhibitor
본 발명은 (i) 신규한 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체를 제공한다:The present invention provides (i) a novel compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
[화학식 I](I)
상기 식에서,In this formula,
R1은 수소, 할로겐 또는 C1-6알킬이고;R 1 is hydrogen, halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소, 하이드록시C1-6알킬, 아미노카본일, C1-6알콕시카본일 또는 카복시이고;R 5 is hydrogen, hydroxyC 1-6 alkyl, aminocarbonyl, C 1-6 alkoxycarbonyl or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X는 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y는 -CH2-, -O- 또는 -N(R7)-이되, R7은 수소, C1-6알킬, 할로C1-6알킬, C3-7사이클로알킬-CmH2m-, C1-6알콕시카본일-CmH2m-, -CtH2t-COOH, -할로C1-6알킬-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CtH2t-, 카복시스피로[3.3]헵틸, 카복시페닐-CmH2m- 또는 카복시피리딘일-CmH2m-이고;Y is -CH 2 -, -O- or -N (R 7) - provided that, R 7 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m - , -C 1-6 alkoxycarbonyl-C m H 2m- , -C t H 2t -COOH, -haloC 1-6 alkyl-COOH, - (C 1-6 alkoxy) C 1-6 alkyl-COOH, - C 1-6 alkyl, -OC 1-6 alkyl, -COOH, -C 3-7 cycloalkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, hydroxy -C t H 2t -, carboxy-spiro [3.3] heptyl, carboxyphenyl -C m H 2m - or carboxy pyridinyl -C m H 2m -, and;
W는 -CH2-, -C(C1-6알킬)2-, -O- 또는 카본일이고;W is -CH 2 -, -C (C 1-6 alkyl) 2 -, -O- or carbonyl;
n은 0 또는 1이고;n is 0 or 1;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 또 다른 실시양태는 (ii) 하기 정의를 갖는 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition: (ii)
R1이 수소, 클로로, 브로모 또는 메틸이고;R 1 is hydrogen, chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소, 클로로 또는 플루오로이고;R < 3 > is hydrogen, chloro or fluoro;
R4가 메틸, 에틸 또는 프로필이고;R < 4 > is methyl, ethyl or propyl;
R5가 수소, 하이드록시메틸, 아미노카본일, 메톡시카본일 또는 카복시이고;R < 5 > is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -CH2-, -O- 또는 -N(R7)-이되, R7이 수소, 메틸, 다이플루오로에틸, 이소프로필, 이소부틸, t-부틸, 사이클로프로필, 사이클로프로필메틸, 메틸-O-카본일이소프로필, 카복시에틸, 카복시다이플루오로에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시(메틸)에틸, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸, 카복시사이클로부틸메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 하이드록시에틸, 하이드록시메틸(젬다이메틸)부틸, 하이드록시(젬다이메틸)에틸, 카복시페닐, 카복시피리딘일 또는 카복시페닐메틸이고;Y is -CH 2 -, -O- or -N (R 7) - provided that, R 7 is hydrogen, methyl, difluoro ethyl, isopropyl, isobutyl, t- butyl, cyclopropyl, cyclopropylmethyl, methyl Carboxy (methyl) ethyl, carboxy (gemidemethyl) propyl, carboxy (gemethyl) methyl, carboxy (Methyl) ethyl, carboxy (ethyl) ethyl, carboxy (methoxy) ethyl, carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclohexyl, carboxycyclohexyl, carboxymethylcyclopropyl, , Carboxycyclobutylmethyl, carboxy spiro [3.3] heptyl, carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl, hydroxymethyl (gemidemethyl) butyl, Pyridinyl or Carboxyphenylmethyl;
W가 -CH2-, -C(CH3)2-, -O- 또는 카본일이고;W is -CH 2 -, -C (CH 3 ) 2 -, -O- , or a carbonyl;
n이 0 또는 1이다.n is 0 or 1.
본 발명의 또 다른 실시양태는 (iii) 하기 화학식 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (IA), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (iii)
[화학식 IA]≪ RTI ID = 0.0 &
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소, 하이드록시C1-6알킬, 아미노카본일, C1-6알콕시카본일 또는 카복시이고;R 5 is hydrogen, hydroxyC 1-6 alkyl, aminocarbonyl, C 1-6 alkoxycarbonyl or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
Y는 -N(R7)-이되, R7은 수소, C1-6알킬, 할로C1-6알킬, C3-7사이클로알킬-CmH2m-, C1-6알콕시카본일-CmH2m-, -CtH2t-COOH, -할로C1-6알킬-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CtH2t-, 카복시스피로[3.3]헵틸, 카복시페닐-CmH2m- 또는 카복시피리딘일-CmH2m-이고;Y is -N (R 7 ) -, wherein R 7 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl-C m H 2m -, C 1-6 alkoxycarbonyl- C m H 2m -, -C t H 2t -COOH, - halo-C 1-6 alkyl, -COOH, - (C 1-6 alkoxy) C 1-6 alkyl, -COOH, -C 1-6 alkyl, -OC 1- 6 alkyl, -COOH, -C 3-7 cycloalkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, hydroxy -C t H 2t -, carboxy-spiro [3.3] heptyl , carboxyphenyl -C m H 2m - or carboxy pyridinyl -C m H 2m -, and;
W은 -CH2- 또는 카본일이고;W is -CH 2 - or carbonyl, and;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 추가 실시양태는 (iv) 하기 정의를 갖는 화학식 I 또는 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Further embodiments of the invention are: (iv) compounds of formula I or IA, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, having the following definitions:
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소, 클로로 또는 플루오로이고;R < 3 > is hydrogen, chloro or fluoro;
R4가 메틸, 에틸 또는 프로필이고;R < 4 > is methyl, ethyl or propyl;
R5가 수소, 하이드록시메틸, 아미노카본일, 메톡시카본일 또는 카복시이고;R < 5 > is hydrogen, hydroxymethyl, aminocarbonyl, methoxycarbonyl or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
Y가 -N(R7)-이되, R7이 수소, 메틸, 다이플루오로에틸, 이소프로필, 이소부틸, t-부틸, 사이클로프로필, 사이클로프로필메틸, 메틸-O-카본일이소프로필, 카복시에틸, 카복시다이플루오로에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시(메틸)에틸, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸, 카복시사이클로부틸메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 하이드록시에틸, 하이드록시메틸(젬다이메틸)부틸, 하이드록시(젬다이메틸)에틸, 카복시페닐, 카복시피리딘일 또는 카복시페닐메틸이고;Y is -N (R 7) - provided that, R 7 is hydrogen, methyl, difluoro ethyl, isopropyl, isobutyl, t- butyl, cyclopropyl, cyclopropylmethyl, methyl isopropyl -O- carbonyl, carboxy Carboxy (methyl) ethyl, carboxy difluoroethyl, carboxypropyl, carboxybutyl, carboxy (gemdimethyl) methyl, carboxy (S) selected from the group consisting of ethyl, carboxy (ethyl) ethyl, carboxy (methoxy) ethyl, carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclohexyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclobutylmethyl, 3.3] heptyl, carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl, hydroxymethyl (gemedimethyl) butyl, hydroxy (gemidemethyl) ethyl, carboxyphenyl, carboxypyridinyl or carboxyphenyl And;
W가 -CH2- 또는 카본일이다.Or a carbonyl - W is -CH 2.
본 발명의 또 다른 실시양태는 (v) 하기 화학식 IAA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula IAA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (v)
[화학식 IAA](IAA)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소, 아미노카본일 또는 카복시이고;R < 5 > is hydrogen, aminocarbonyl or carboxy;
R6은 수소이고;R < 6 > is hydrogen;
R7은 C1-6알킬, 할로C1-6알킬, C3-7사이클로알킬, C3-7사이클로알킬-CmH2m-, -CtH2t-COOH, -CmH2m-C3-7사이클로알킬-COOH 또는 카복시페닐이고; R 7 is C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C m H 2m -, -C t H 2t -COOH, -C m H 2m- C 3-7 cycloalkyl-COOH or carboxyphenyl;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 추가 실시양태는 (vi) 하기 정의를 갖는 화학식 I, IA 또는 IAA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:(Vi) a compound of formula (I), (IA) or (IAA), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition:
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소, 아미노카본일 또는 카복시이고;R < 5 > is hydrogen, aminocarbonyl or carboxy;
R6이 수소이고;R < 6 > is hydrogen;
R7이 메틸, 이소프로필, 이소부틸, t-부틸, 다이플루오로에틸, 사이클로프로필, 사이클로프로필메틸, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸 또는 카복시페닐이다.R 7 is selected from the group consisting of methyl, isopropyl, isobutyl, t-butyl, difluoroethyl, cyclopropyl, cyclopropylmethyl, carboxy (gemidemethyl) ethyl, carboxy (gemidemethyl) propyl, carboxycyclopropylmethyl, Butylmethyl or carboxyphenyl.
본 발명의 또 다른 실시양태는 (vii) 하기 화학식 IB의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention are: (vii) Compounds of formula IB, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof,
[화학식 IB](IB)
상기 식에서,In this formula,
R1은 수소 또는 할로겐이고;R < 1 > is hydrogen or halogen;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소이고;R < 5 > is hydrogen;
R6은 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y는 -CH2- 또는 -O-이고;Y is -CH 2 - or -O-;
W는 -CH2-, -C(C1-6알킬)2- 또는 -O-이고;W is -CH 2 -, -C (C 1-6 alkyl) 2 - or -O-;
n은 0 또는 1이다.n is 0 or 1;
본 발명의 추가 실시양태는 (viii) 하기 정의를 갖는 화학식 I 또는 IB의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is: (viii) a compound of formula I or IB, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition:
R1이 수소, 클로로 또는 브로모이고;R < 1 > is hydrogen, chloro or bromo;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소이고;R < 5 > is hydrogen;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -CH2- 또는 -O-이고;Y is -CH 2 - or -O-;
W가 -CH2-, -C(CH3)2- 또는 -O-이고;W is -CH 2 -, -C (CH 3 ) 2 - or -O-;
n이 0 또는 1이다.n is 0 or 1.
본 발명의 또 다른 실시양태는 (ix) 하기 화학식 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (ID), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (ix)
[화학식 ID][Chemical Formula I]
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소, 아미노카본일 또는 카복시이고;R < 5 > is hydrogen, aminocarbonyl or carboxy;
R6은 수소 또는 C1-6알콕시카본일이고;R 6 is hydrogen or C 1-6 alkoxycarbonyl and;
X는 카본일이고;X is carbonyl;
Y는 -O-, -CH2- 또는 -N(R7)-이되, R7은 수소, C1-6알킬, 할로C1-6알킬, C3-7사이클로알킬, C3-7사이클로알킬-CmH2m-, -CtH2t-COOH -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CtH2t-, 카복시스피로[3.3]헵틸 또는 카복시페닐-CmH2m-이고;Y is -O-, -CH 2 - or -N (R 7) - provided that, R 7 is hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl Alkyl-C m H 2m -, -C t H 2t -COOH -C m H 2m -C 3-7 cycloalkyl-COOH, hydroxy-C t H 2t -, carboxy spiro [3.3] heptyl or carboxyphenyl- m H 2m -;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 추가 실시양태는 (x) 하기 정의를 갖는 화학식 I 또는 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the invention are the compounds of formula (I) or (ID), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (x)
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸, 에틸 또는 프로필이고;R < 4 > is methyl, ethyl or propyl;
R5가 수소, 아미노카본일 또는 카복시이고;R < 5 > is hydrogen, aminocarbonyl or carboxy;
R6이 수소 또는 메틸-O-카본일이고;R < 6 > is hydrogen or methyl-O-carbonyl;
X가 카본일이고;X is carbonyl;
Y가 -O-, -CH2- 또는 -N(R7)-이되, R7이 수소, 메틸, 이소프로필, 다이플루오로에틸, 이소부틸, t-부틸, 사이클로프로필, 사이클로프로필메틸, 카복시(젬다이메틸)에틸, 카복시(메틸)에틸, 카복시사이클로프로필메틸, 카복시페닐, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 하이드록시에틸, 하이드록시(젬다이메틸)에틸 또는 카복시페닐메틸이다.Y is -O-, -CH 2 - or -N (R 7) - provided that, R 7 is hydrogen, methyl, isopropyl, difluoro ethyl, isobutyl, t- butyl, cyclopropyl, cyclopropylmethyl, carboxy (Gemdimethyl) ethyl, carboxy (methyl) ethyl, carboxycyclopropylmethyl, carboxyphenyl, carboxycyclopentyl, carboxycyclohexyl, carboxy Carboxy spiro [3.3] heptyl, hydroxyethyl, hydroxy (gemedimethyl) ethyl or carboxyphenylmethyl.
본 발명의 또 다른 실시양태는 (xi) 하기 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is (xi) a compound of formula IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:
[화학식 IE](IE)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -O-, -CH2- 또는 -N(R7)-이되, R7은 C1-6알킬, C3-7사이클로알킬, -CtH2t-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, 카복시스피로[3.3]헵틸 또는 카복시페닐-CmH2m-이고; Y is -O-, -CH 2 - or -N (R 7 ) -, wherein R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, -C t H 2t -COOH, -C 3-7 cyclo alkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, - (C 1-6 alkoxy) C 1-6 alkyl, -COOH, -C 1-6 alkyl, -OC 1- 6 alkyl, -COOH, carboxy-spiro [3.3] heptyl or carboxyphenyl -C m H 2m -, and;
W는 -CH2- 또는 -C(C1-6알킬)2-이고;W is -CH 2 - or -C (C 1-6 alkyl) 2 -;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 추가 실시양태는 (xii) 하기 정의를 갖는 화학식 I 또는 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is (xii) a compound of formula I or IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition:
R1이 클로로 또는 메틸이고; R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -O-, -CH2- 또는 -N(R7)-이되, R7이 이소프로필, 메틸, 이소부틸, t-부틸, 사이클로프로필, 카복시에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(메틸)에틸, 카복시사이클로부틸, 카복시사이클로프로필메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시(젬다이메틸)프로필, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 카복시페닐메틸 또는 카복시페닐이고;Y is -O-, -CH 2 - or -N (R 7) - provided that, R 7 is isopropyl, methyl, isobutyl, t- butyl, cyclopropyl, ethyl carboxy, propyl carboxy, carboxy-butyl, carboxy (Gem (Dimethylamino) methyl, carboxy (gemidemethyl) ethyl, carboxy (methyl) ethyl, carboxycyclobutyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxy (Ethyl) ethyl, carboxy (methoxy) ethyl, carboxycyclobutylmethyl, carboxy spiro [3.3] heptyl, carboxymethoxyethyl, carboxymethoxypropyl, carboxyphenylmethyl or carboxyphenyl;
W가 -CH2- 또는 -C(CH3)2-이다.W is -CH 2 - or -C (CH 3 ) 2 -.
본 발명의 또 다른 실시양태는 (xiii) 하기 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is (xiii) a compound of formula IE: or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:
[화학식 IE](IE)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -N(R7)-이되, R7은 수소, C1-6알킬, C3-7사이클로알킬, -CtH2t-COOH, -CmH2m-C3-7사이클로알킬-COOH 또는 카복시페닐이고; Y is -N (R 7 ) -, wherein R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, -C t H 2t -COOH, -C m H 2m -C 3-7 cycloalkyl- COOH or carboxyphenyl;
W는 -CH2-이고;W is -CH 2 - and;
m은 0 내지 7이고;m is 0 to 7;
t는 1 내지 7이다.t is from 1 to 7;
본 발명의 추가 실시양태는 (xiv) 하기 정의를 갖는 화학식 I 또는 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula I or IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (xiv)
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -N(R7)-이되, R7이 수소, 메틸, t-부틸, 사이클로프로필, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시(메틸)에틸, 카복시사이클로프로필메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시사이클로부틸메틸 또는 카복시페닐이고;Y is -N (R 7) - provided that, R 7 is hydrogen, methyl, t- butyl, cyclopropyl, carboxy (gem-dimethyl) ethyl, carboxy (gem-dimethyl) propyl, carboxy (methyl) ethyl, carboxy-cyclopropyl Methyl, carboxycyclopentyl, carboxycyclohexyl, carboxycyclobutylmethyl or carboxyphenyl;
W가 -CH2-이다.W is -CH 2 - is.
본 발명의 또 다른 실시양태는 (xv) 하기 정의를 갖는 화학식 I, IA, IAA, IB, ID 또는 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the invention are the compounds of formula I, IA, IAA, IB, ID or IE, or pharmaceutically acceptable salts, enantiomers or diastereoisomers thereof,
2-티아졸릴 기가 C1-6알킬로 추가 치환되고;The 2-thiazolyl group is further substituted by C 1-6 alkyl;
다른 치환기가 모두 상기와 같이 정의된다.All other substituents are defined as above.
본 발명의 추가 실시양태는 (xvi) 하기 정의를 갖는 화학식 I, IA, IAA, IB, ID 또는 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula (I), (IA), (IA), (IB), (ID) IA or IB, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
2-티아졸릴 기가 메틸로 추가 치환되고;The 2-thiazolyl group is further substituted with methyl;
다른 치환기가 모두 상기와 같이 정의된다.All other substituents are defined as above.
본 발명의 또 다른 실시양태는 (xvii) 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (xvii)
[화학식 I](I)
상기 식에서,In this formula,
R1은 수소, 할로겐 또는 C1-6알킬이고;R 1 is hydrogen, halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X는 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y는 -CH2-, -O- 또는 -N(R7)-이되, R7은 수소, C1-6알킬, C3-7사이클로알킬, C1-6알콕시카본일-CmH2m-, -CmH2m-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CmH2m-, 카복시스피로[3.3]헵틸 또는 카복시페닐-CmH2m-이고;Y is -CH 2 -, -O- or -N (R 7) - provided that, R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxycarbonyl -C m H 2m -, -C m H 2m -COOH, - (C 1-6 alkoxy) C 1-6 alkyl-COOH, -C 1-6 alkyl-OC 1-6 alkyl-COOH, -C 3-7 cycloalkyl-C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl-COOH, hydroxy-C m H 2m -, carboxy spiro [3.3] heptyl or carboxyphenyl-C m H 2m -;
W는 -CH2-, -C(C1-6알킬)2-, -O- 또는 카본일이고;W is -CH 2 -, -C (C 1-6 alkyl) 2 -, -O- or carbonyl;
n은 0 또는 1이고;n is 0 or 1;
m은 0 내지 7이다.m is 0 to 7;
본 발명의 추가 실시양태는 (xviii) 하기 정의를 갖는 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the invention are the compounds of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (xviii)
R1이 수소, 클로로, 브로모 또는 메틸이고;R 1 is hydrogen, chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소, 클로로 또는 플루오로이고;R < 3 > is hydrogen, chloro or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -CH2-, -O- 또는 -N(R7)-이되, R7이 수소, 메틸, 이소프로필, t-부틸, 사이클로프로필, 메틸-O-카본일이소프로필, 카복시에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시(메틸)에틸, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸, 카복시사이클로부틸메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 하이드록시에틸, 하이드록시메틸(젬다이메틸)부틸, 카복시페닐 또는 카복시페닐메틸이고;Y is -CH 2 -, -O- or -N (R 7) - provided that, R 7 is hydrogen, methyl, isopropyl, t- butyl, cyclopropyl, methyl-carbonyl -O- isopropyl, carboxyethyl, carboxy Carboxy (methyl) ethyl, carboxy (ethyl) ethyl, carboxy (dimethylamino) ethyl, carboxy (gemidemethyl) (Methoxy) ethyl, carboxycyclobutyl, carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl, carboxy spiro [3.3] heptyl, carboxymethoxyethyl, Carboxymethoxypropyl, hydroxyethyl, hydroxymethyl (gemedimethyl) butyl, carboxyphenyl or carboxyphenylmethyl;
W가 -CH2-, -C(CH3)2-, -O- 또는 카본일이고;W is -CH 2 -, -C (CH 3 ) 2 -, -O- , or a carbonyl;
n이 0 또는 1이다.n is 0 or 1.
본 발명의 또 다른 실시양태는 (xix) 하기 화학식 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (IA), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
[화학식 IA]≪ RTI ID = 0.0 &
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
Y는 -N(R7)-이되, R7은 수소, C1-6알킬, C3-7사이클로알킬, C1-6알콕시카본일-CmH2m-, -CmH2m-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CmH2m-, 카복시스피로[3.3]헵틸 또는 카복시페닐-CmH2m-이고;Y is -N (R 7) - provided that, R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxycarbonyl -C m H 2m -, -C m H 2m -COOH , - (C 1-6 alkoxy) C 1-6 alkyl-COOH, -C 1-6 alkyl-OC 1-6 alkyl-COOH, -C 3-7 cycloalkyl-C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl-COOH, hydroxy-C m H 2m -, carboxy spiro [3.3] heptyl or carboxyphenyl-C m H 2m -;
W는 -CH2- 또는 카본일이고;W is -CH 2 - or carbonyl, and;
m은 0 내지 7이다.m is 0 to 7;
본 발명의 추가 실시양태는 (xx) 하기 정의를 갖는 화학식 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein (xx)
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소, 클로로 또는 플루오로이고;R < 3 > is hydrogen, chloro or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
Y가 -N(R7)-이되, R7이 수소, 메틸, 이소프로필, t-부틸, 사이클로프로필, 메틸-O-카본일이소프로필, 카복시에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시(메틸)에틸, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸, 카복시사이클로부틸메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 하이드록시에틸, 하이드록시메틸(젬다이메틸)부틸, 카복시페닐 또는 카복시페닐메틸이고;Y is -N (R 7) - provided that, R 7 is hydrogen, methyl, isopropyl, t- butyl, cyclopropyl, methyl-carbonyl -O- isopropyl, carboxy-ethyl, carboxy-propyl, carboxy-butyl, carboxy (gem dimethyl Carboxy (methyl) methyl, carboxy (gemidemethyl) ethyl, carboxy (gemidemethyl) propyl, carboxy , Carboxycyclobutylmethyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl, carboxy spiro [3.3] heptyl, carboxymethoxyethyl, carboxymethoxypropyl, hydroxyethyl, Butyl, hydroxymethyl (gemdimethyl) butyl, carboxyphenyl or carboxyphenylmethyl;
W가 -CH2- 또는 카본일이다.Or a carbonyl - W is -CH 2.
본 발명의 또 다른 실시양태는 (xxi) 하기 화학식 IAA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is (xxi) a compound of formula IAA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein:
[화학식 IAA](IAA)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소이고;R < 6 > is hydrogen;
R7은 C1-6알킬, C3-7사이클로알킬, -CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH 또는 카복시페닐이고; R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl-COOH or carboxyphenyl;
m은 1 내지 6이다.m is 1 to 6;
본 발명의 추가 실시양태는 (xxii) 하기 정의를 갖는 화학식 IAA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the invention is a compound of formula IAA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxii):
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소이고;R < 6 > is hydrogen;
R7이 메틸, 이소프로필, t-부틸, 사이클로프로필, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸 또는 카복시페닐이다.R 7 is methyl, isopropyl, t-butyl, cyclopropyl, carboxy (gemethyl) ethyl, carboxy (gemidemethyl) propyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl.
본 발명의 또 다른 실시양태는 (xxiii) 하기 화학식 IC의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the invention are the compounds of formula (Ic), (xxiii), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
[화학식 IC]≪ EMI ID =
상기 식에서,In this formula,
R1은 할로겐이고;R < 1 > is halogen;
R2는 수소이고;R 2 is hydrogen;
R3은 할로겐이고;R < 3 > is halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소이고;R < 5 > is hydrogen;
R6은 수소이고;R < 6 > is hydrogen;
R7은 수소이고; R < 7 > is hydrogen;
W는 -CH2-이다.W is -CH 2 - is.
본 발명의 또 다른 실시양태는 (xxiv) 하기 화학식 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula ID: (xxiv), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
[화학식 ID][Chemical Formula I]
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 C1-6알콕시카본일이고;R 6 is hydrogen or C 1-6 alkoxycarbonyl and;
X는 카본일이고;X is carbonyl;
Y는 -O- 또는 -N(R7)-이되, R7은 수소, C1-6알킬, C3-7사이클로알킬, -CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 하이드록시-CmH2m-, 카복시스피로[3.3]헵틸 또는 카복시페닐-CtH2t-이고;Y is -O- or -N (R 7 ) -, wherein R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m -COOH, -C m H 2m- C 3- 7 cycloalkyl, -COOH, hydroxy -C m H 2m -, carboxy-spiro [3.3] heptyl or carboxyphenyl -C t H 2t -, and;
m은 1 내지 6이고;m is 1 to 6;
t는 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xxv) 하기 정의를 갖는 화학식 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula ID, (xxv), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition:
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 메틸-O-카본일이고;R < 6 > is hydrogen or methyl-O-carbonyl;
X가 카본일이고;X is carbonyl;
Y가 -O- 또는 -N(R7)-이되, R7이 수소, 메틸, 이소프로필, t-부틸 사이클로프로필, 카복시(젬다이메틸)에틸, 카복시(메틸)에틸, 카복시사이클로프로필메틸, 카복시페닐, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 하이드록시에틸 또는 카복시페닐메틸이다.Y is -O- or -N (R 7) - provided that, R 7 is hydrogen, methyl, isopropyl, t- butyl, cyclopropyl, carboxy (gem-dimethyl) ethyl, carboxy (methyl) ethyl, carboxy-methyl-cyclopropyl, Carboxycyclohexyl, carboxy (gemidemethyl) propyl, carboxy (gemedimethyl) butyl, carboxycyclobutylmethyl, carboxy spiro [3.3] heptyl, hydroxyethyl or carboxyphenylmethyl.
본 발명의 또 다른 실시양태는 (xxvi) 하기 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (IE), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein (xxvi)
[화학식 IE](IE)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -O- 또는 -N(R7)-이되, R7은 C1-6알킬, C3-7사이클로알킬, -CmH2m-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, 카복시스피로[3.3]헵틸 또는 카복시페닐-CmH2m-이고; Y is -O- or -N (R 7 ) -, wherein R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m -COOH, -C 3-7 cycloalkyl-C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, - (C 1-6 alkoxy) C 1-6 alkyl, -COOH, -C 1-6 alkyl, -OC 1-6 alkyl, -COOH, carboxy-spiro [3.3] heptyl or carboxyphenyl -C m H 2m -, and;
W는 -CH2- 또는 -C(C1-6알킬)2-이고;W is -CH 2 - or -C (C 1-6 alkyl) 2 -;
m은 0 내지 6이다.m is 0 to 6;
본 발명의 추가 실시양태는 (xxvii) 하기 정의를 갖는 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxvii):
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -O- 또는 -N(R7)-이되, R7이 이소프로필, 메틸, t-부틸, 사이클로프로필, 카복시에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(메틸)에틸, 카복시사이클로부틸, 카복시사이클로프로필메틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시메틸사이클로프로필, 카복시(젬다이메틸)프로필, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸메틸, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 카복시페닐메틸 또는 카복시페닐이고;Y is -O- or -N (R 7) - provided that, R 7 is isopropyl, methyl, t- butyl, cyclopropyl, ethyl carboxy, propyl carboxy, carboxy-butyl, carboxy (gem dimethyl) methyl, carboxy (Gem Carboxy (methyl) ethyl, carboxy (methyl) ethyl, carboxycyclobutyl, carboxycyclopropylmethyl, carboxycyclopentyl, carboxycyclohexyl, carboxymethylcyclopropyl, carboxy Carboxypropylmethyl, carboxypropylmethyl, carboxymethylmethyl, carboxymethylmethyl, carboxymethylmethyl, carboxymethylmethyl, carboxymethylmethyl, carboxymethylmethyl,
W가 -CH2- 또는 -C(CH3)2-이다.W is -CH 2 - or -C (CH 3 ) 2 -.
본 발명의 또 다른 실시양태는 (xxviii) 하기 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the invention are the compounds of formula (IE), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, of formula (xxviii)
[화학식 IE](IE)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -O-, -CH2- 또는 -N(R7)-이되, R7은 C1-6알킬, C3-7사이클로알킬, -CmH2m-COOH, -C3-7사이클로알킬-CmH2m-COOH, -CmH2m-C3-7사이클로알킬-COOH, 카복시스피로[3.3]헵틸, -(C1-6알콕시)C1-6알킬-COOH, -C1-6알킬-O-C1-6알킬-COOH, 카복시피리딘일-CmH2m- 또는 카복시페닐-CmH2m-이고;Y is -O-, -CH 2 - or -N (R 7) - provided that, R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, -C m H 2m -COOH, -C 3-7 cycloalkyl alkyl, -C m H 2m -COOH, -C m H 2m -C 3-7 cycloalkyl, -COOH, carboxy-spiro [3.3] heptyl, - (C 1-6 alkoxy) C 1-6 alkyl, -COOH, -C 1 -6 alkyl, -OC 1-6 alkyl, -COOH, carboxy-pyridinyl, -C m H 2m - or carboxyphenyl -C m H 2m -, and;
W는 -CH2- 또는 -C(C1-6알킬)2-이고;W is -CH 2 - or -C (C 1-6 alkyl) 2 -;
m은 0 내지 6이다.m is 0 to 6;
본 발명의 추가 실시양태는 (xxix) 하기 정의를 갖는 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxix):
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -O-, -CH2- 또는 -N(R7)-이되, R7이 메틸, t-부틸, 이소프로필, 사이클로프로필, 카복시에틸, 카복시프로필, 카복시부틸, 카복시(젬다이메틸)메틸, 카복시(젬다이메틸)에틸, 카복시(메틸)에틸, 카복시사이클로부틸, 카복시사이클로펜틸, 카복시사이클로헥실, 카복시사이클로프로필메틸, 카복시(젬다이메틸)프로필, 카복시(젬다이메틸)부틸, 카복시(에틸)에틸, 카복시(메톡시)에틸, 카복시사이클로부틸메틸, 카복시메틸사이클로프로필, 카복시스피로[3.3]헵틸, 카복시메톡시에틸, 카복시메톡시프로필, 카복시페닐메틸, 카복시피리딘일 또는 카복시페닐이고;Y is -O-, -CH 2 - or -N (R 7) - provided that, R 7 is methyl, t- butyl, isopropyl, cyclopropyl, ethyl carboxy, propyl carboxy, carboxy-butyl, carboxy (gem dimethyl) Carboxy (methyl) ethyl, carboxy (methyl) ethyl, carboxycyclobutyl, carboxycyclohexyl, carboxycyclohexyl, carboxycyclopropylmethyl, Is selected from the group consisting of (ethyl) ethyl, carboxy (methoxy) ethyl, carboxycyclobutylmethyl, carboxymethylcyclopropyl, carboxy spiro [3.3] heptyl, carboxymethoxyethyl, carboxymethoxypropyl, carboxyphenylmethyl, carboxypyridinyl or carboxyphenyl ;
W가 -CH2- 또는 -C(CH3)2-이다.W is -CH 2 - or -C (CH 3 ) 2 -.
본 발명은 (xxx) 하기 화학식 I의 신규한 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체를 제공한다:The present invention provides (xxx) a novel compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
[화학식 I](I)
상기 식에서,In this formula,
R1은 수소, 할로겐 또는 C1-6알킬이고;R 1 is hydrogen, halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X는 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y는 -CH2-, -O-, -NR7 또는 -N-R8-COOH이되, Y is -CH 2 -, -O-, -NR 7 or -NR 8 -COOH,
R7은 수소, C1-6알킬, C3-7사이클로알킬 또는 C1-6알콕시카본일-CmH2m-이고,R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 1-6 alkoxycarbonyl-C m H 2m -
R8은 -CmH2m-, -CtH2t-C3-7사이클로알킬-CtH2t- 또는 페닐이고; R 8 is -C m H 2m -, -C t H 2t -C 3-7 cycloalkyl-C t H 2t - or phenyl;
W는 -CH2-, -O- 또는 카본일이고;W is -CH 2 -, -O-, or a carbonyl;
n은 0 또는 1이고;n is 0 or 1;
m은 1 내지 6이고;m is 1 to 6;
t는 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xxxi) 하기 정의를 갖는 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the invention are the compounds of formula (I), or pharmaceutically acceptable salts, enantiomers or diastereoisomers thereof, wherein: (xxxi)
R1이 수소, 클로로, 브로모 또는 메틸이고;R 1 is hydrogen, chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -CH2-, -O- , -NR7 또는 -N-R8-COOH이되,Y is -CH 2 -, -O-, -NR 7 or -NR 8 -COOH,
R7이 수소, 이소프로필, 사이클로프로필 또는 메틸-O-카본일이소프로필이고,R 7 is hydrogen, isopropyl, cyclopropyl or methyl-O-carbonylisopropyl,
R8이 에틸, 프로필, (젬다이메틸)메틸, (젬다이메틸)에틸, (메틸)에틸, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 메틸사이클로프로필, 사이클로프로필메틸, 사이클로부틸메틸 또는 페닐이고;R 8 is ethyl, propyl, (gemidemethyl) methyl, (gemidemethyl) ethyl, (methyl) ethyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, cyclopropylmethyl, cyclobutylmethyl or phenyl;
W가 -CH2-, -O- 또는 카본일이고;W is -CH 2 -, -O-, or a carbonyl;
n이 0 또는 1이다.n is 0 or 1.
본 발명의 또 다른 실시양태는 (xxxii) 하기 정의를 갖는 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxxii):
R1이 수소, 할로겐 또는 C1-6알킬이고;R 1 is hydrogen, halogen or C 1-6 alkyl;
R2가 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3이 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4가 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -CH2-, -O-, -NR7 또는 -N-R8-COOH이되,Y is -CH 2 -, -O-, -NR 7 or -NR 8 -COOH,
R7이 수소, C1-6알킬, C3-7사이클로알킬 또는 C1-6알콕시카본일-CmH2m-이고,R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 1-6 alkoxycarbonyl-C m H 2m -
R8이 -CmH2m-, C3-7사이클로알킬-CtH2t- 또는 페닐이고;R 8 is -C m H 2m -, C 3-7 cycloalkyl-C t H 2t - or phenyl;
W가 -CH2-, -O- 또는 카본일이고;W is -CH 2 -, -O-, or a carbonyl;
n이 0 또는 1이고;n is 0 or 1;
m이 1 내지 6이고;m is from 1 to 6;
t가 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xxxiii) 하기 정의를 갖는 화학식 I의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxxiii):
R1이 수소, 클로로, 브로모 또는 메틸이고;R 1 is hydrogen, chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -CH2-, -O-, -NR7 또는 -N-R8-COOH이되,Y is -CH 2 -, -O-, -NR 7 or -NR 8 -COOH,
R7이 수소, 이소프로필, 사이클로프로필 또는 메틸-O-카본일이소프로필이고,R 7 is hydrogen, isopropyl, cyclopropyl or methyl-O-carbonylisopropyl,
R8이 (젬다이메틸)메틸, (젬다이메틸)에틸, (메틸)에틸, 사이클로부틸, 사이클로프로필메틸 또는 페닐이고;R 8 is (gemedimethyl) methyl, (gemidemethyl) ethyl, (methyl) ethyl, cyclobutyl, cyclopropylmethyl or phenyl;
W가 -CH2-, -O- 또는 카본일이고;W is -CH 2 -, -O-, or a carbonyl;
n이 0 또는 1이다.n is 0 or 1.
본 발명의 또 다른 실시양태는 (xxxiv) 하기 화학식 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is (xxxiv) a compound of formula (IA), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
[화학식 IA]≪ RTI ID = 0.0 &
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
Y는 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7은 수소, C1-6알킬, C3-7사이클로알킬 또는 C1-6알콕시카본일-CmH2m-이고,R 7 is hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 1-6 alkoxycarbonyl-C m H 2m -
R8은 -CmH2m-, C3-7사이클로알킬-CtH2t- 또는 페닐이고; R 8 is -C m H 2m -, C 3-7 cycloalkyl-C t H 2t - or phenyl;
W는 -CH2- 또는 카본일이고;W is -CH 2 - or carbonyl, and;
m은 1 내지 6이고;m is 1 to 6;
t는 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xxxv) 하기 정의를 갖는 화학식 IA의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxxv):
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
Y가 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7이 수소, 이소프로필, 사이클로프로필 또는 메틸-O-카본일이소프로필이고,R 7 is hydrogen, isopropyl, cyclopropyl or methyl-O-carbonylisopropyl,
R8이 (젬다이메틸)메틸, (젬다이메틸)에틸, (메틸)에틸, 사이클로부틸, 사이클로프로필메틸 또는 페닐이고;R 8 is (gemedimethyl) methyl, (gemidemethyl) ethyl, (methyl) ethyl, cyclobutyl, cyclopropylmethyl or phenyl;
W가 -CH2- 또는 카본일이다.Or a carbonyl - W is -CH 2.
본 발명의 또 다른 실시양태는 (xxxvi) 하기 화학식 IAB의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (IAB), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (xxxvi)
[화학식 IAB](IAB)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소이고;R < 5 > is hydrogen;
R6은 수소이고;R < 6 > is hydrogen;
R8은 -CmH2m-, C3-7사이클로알킬-CmH2m- 또는 페닐이고; R 8 is -C m H 2m -, C 3-7 cycloalkyl-C m H 2m - or phenyl;
m은 1 내지 6이다.m is 1 to 6;
본 발명의 추가 실시양태는 (xxxvii) 하기 정의를 갖는 화학식 IAB의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula (IAB), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition (xxxvii):
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소이고;R < 5 > is hydrogen;
R6이 수소이고;R < 6 > is hydrogen;
R8이 (젬다이메틸)에틸, 사이클로프로필메틸 또는 페닐이다.R 8 is (gemidemethyl) ethyl, cyclopropylmethyl or phenyl.
본 발명의 또 다른 실시양태는 (xxxviii) 하기 화학식 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula ID: (xxxviii), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
[화학식 ID][Chemical Formula I]
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소, C1-6알콕시카본일 또는 카복시-CmH2m-이고;R 6 is hydrogen, C 1-6 alkoxycarbonyl or carboxy-C m H 2m -;
X는 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y는 -O-, -NR7 또는 -N-R8-COOH이되,Y is -O-, -NR 7 or -NR 8 -COOH,
R7은 수소, C1-6알킬 또는 C3-7사이클로알킬이고,R 7 is hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl,
R8은 -CmH2m-, C3-7사이클로알킬-CtH2t- 또는 페닐이고;R 8 is -C m H 2m -, C 3-7 cycloalkyl-C t H 2t - or phenyl;
m은 1 내지 6이고;m is 1 to 6;
t는 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xxxix) 하기 정의를 갖는 화학식 ID의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula ID having the following definition (xxxix), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
R1이 클로로, 브로모 또는 메틸이고;R 1 is chloro, bromo or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소, 메틸-O-카본일 또는 카복시메틸이고;R <6> is hydrogen, methyl-O-carbonyl or carboxymethyl;
X가 카본일 또는 설폰일이고;X is carbonyl or sulfonyl;
Y가 -O-, -NR7 또는 -N-R8-COOH이되,Y is -O-, -NR 7 or -NR 8 -COOH,
R7이 수소, 이소프로필 또는 사이클로프로필이고,R < 7 > is hydrogen, isopropyl or cyclopropyl,
R8이 (젬다이메틸)에틸, (메틸)에틸, 사이클로부틸, 사이클로프로필메틸 또는 페닐이다.R 8 is (gemidemethyl) ethyl, (methyl) ethyl, cyclobutyl, cyclopropylmethyl or phenyl.
본 발명의 또 다른 실시양태는 (xl) 하기 화학식 IF의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다: Another embodiment of the present invention is a compound of formula (IF), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (x1)
[화학식 IF](Formula IF)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7은 C1-6알킬 또는 C3-7사이클로알킬이고,R 7 is C 1-6 alkyl or C 3-7 cycloalkyl,
R8은 -CmH2m-, C3-7사이클로알킬-CtH2t- 또는 페닐이고; R 8 is -C m H 2m -, C 3-7 cycloalkyl-C t H 2t - or phenyl;
m은 1 내지 6이고;m is 1 to 6;
t는 0 내지 6이다.t is from 0 to 6;
본 발명의 추가 실시양태는 (xli) 하기 정의를 갖는 화학식 IF의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IF, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein (xli)
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7이 이소프로필 또는 사이클로프로필이고,R < 7 > is isopropyl or cyclopropyl,
R8이 (젬다이메틸)메틸, (젬다이메틸)에틸, (메틸)에틸, 사이클로부틸, 사이클로프로필메틸 또는 페닐이다.R 8 is (gemedimethyl) methyl, (gemidemethyl) ethyl, (methyl) ethyl, cyclobutyl, cyclopropylmethyl or phenyl.
본 발명의 또 다른 실시양태는 (xlii) 하기 화학식 IF의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Another embodiment of the present invention is a compound of formula (IF), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, wherein: (xlii)
[화학식 IF](Formula IF)
상기 식에서,In this formula,
R1은 할로겐 또는 C1-6알킬이고;R 1 is halogen or C 1-6 alkyl;
R2는 수소 또는 할로겐이고;R < 2 > is hydrogen or halogen;
R3은 수소 또는 할로겐이고;R < 3 > is hydrogen or halogen;
R4는 C1-6알킬이고;R 4 is C 1-6 alkyl;
R5는 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6은 수소 또는 카복시-CmH2m-이고;R 6 is hydrogen or a carboxy -C m H 2m -, and;
Y는 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7은 수소 또는 C3-7사이클로알킬이고,R 7 is hydrogen or C 3-7 cycloalkyl,
R8은 -CmH2m-, C3-7사이클로알킬-CmH2m- 또는 페닐이고; R 8 is -C m H 2m -, C 3-7 cycloalkyl-C m H 2m - or phenyl;
m은 1 내지 6이다.m is 1 to 6;
본 발명의 추가 실시양태는 (xliii) 하기 정의를 갖는 화학식 IE의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula IE, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, having the following definition of (xliii)
R1이 클로로 또는 메틸이고;R 1 is chloro or methyl;
R2가 수소 또는 플루오로이고;R < 2 > is hydrogen or fluoro;
R3이 수소 또는 플루오로이고;R < 3 > is hydrogen or fluoro;
R4가 메틸 또는 에틸이고;R < 4 > is methyl or ethyl;
R5가 수소 또는 카복시이고;R < 5 > is hydrogen or carboxy;
R6이 수소 또는 카복시메틸이고;R < 6 > is hydrogen or carboxymethyl;
Y가 -NR7 또는 -N-R8-COOH이되,Y is -NR 7 or -NR 8 -COOH,
R7이 수소 또는 사이클로프로필이고,R < 7 > is hydrogen or cyclopropyl,
R8이 (젬다이메틸)에틸, (메틸)에틸, 사이클로프로필메틸 또는 페닐이다.R 8 is (gemidemethyl) ethyl, (methyl) ethyl, cyclopropylmethyl or phenyl.
본 발명의 추가 실시양태는 (xliv) 다이하이드로피리미딘 코어의 4 위치에서 키랄성이 하기 화학식 IR과 동일한, 화학식 I, 화학식 IA, 화학식 IAA, 화학식 IB, 화학식 IC, 화학식 ID, 화학식 IE, 화학식 IAB 또는 화학식 IF의 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:A further embodiment of the present invention is a compound of formula I, IA, IAA, IB, IC, ID, IE, IAB, wherein the chirality at the 4 position of the (xliv) dihydropyrimidine core is the same as IR, Or a compound of formula IF, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
[화학식 I](I)
[화학식 IR](IR)
상기 식에서,In this formula,
R1, R2, R3, R4, R5, R6, X, Y, W 및 n은 상기 실시양태 (i) 내지 (xliii) 중 어느 하나에 정의된 바와 같다.R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, W and n are as defined in any of the embodiments (i) to (xliii).
본 발명에 따른 본 발명의 특정한 화합물은 하기 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:Particular compounds of the invention according to the present invention are the following compounds, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof:
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,8,9,9a-헥사하이드로피라지노[1,2-c][1,3]옥사진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(6-oxo-1,3,4,8,9,9a-hexahydropyrazino [ ] [1,3] oxazin-2-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(4-옥소-6,7,9,9a-테트라하이드로-1H-피라지노[2,1-c][1,4]옥사진-8-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;(4-fluoro-phenyl) -6 - [(4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino [ [1,4] oxazin-8-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aR)-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl] -4-methyl-4H-pyrrolo [2,3-c] pyridazin- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aS)-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4- (4-trifluoromethyl-pyrimidin-4-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aS)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4 (4H) -6- [[(8aS) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4 (4H) -6- [[(8aR) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4 (4H) -6- [[(8aR) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-bromo-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4 (4H) -6- [[(8aR) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-bromo-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4S)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(3,4-다이플루오로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl] methyl] -4 < RTI ID = 0.0 > - (3,4-difluorophenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[(6-옥소-3,4,7,8,9,9a-헥사하이드로-1H-피리도[1,2-a]피라진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Chloro-3-fluoro-phenyl) -6 - [(6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido [ 2-a] pyrazin-2-yl) methyl] -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aR)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(8aR) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aS)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(8aS) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-6-[[(8aS)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Ethyl] (4R) -6 - [[(8aS) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-bromo-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-6-[[(8aR)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;(4R) -6 - [[(8aR) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-bromo-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aR)-1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl) methyl] -4- (4-methylpiperazin-1-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8aS)-1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Yl) methyl] -4- (4-methylpiperazin-1-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(3aS)-1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(3aS) -1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [1,2,5] thiadiazolo [ a] pyrazin-5-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(3aR)-1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(3aR) -1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [1,2,5] thiadiazolo [ a] pyrazin-5-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메틸-프로판산;3 - [(8aS) -7 - [[(4R) -4- (2-Chlorophenyl) -5- ethoxycarbonyl-2-thiazol-2-yl-1,4- dihydropyrimidine- -Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] -2-methyl-propanoic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메틸-프로판산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- mountain;
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;Methyl-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid;
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-메톡시-1,1-다이메틸-2-옥소-에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;(2-chloro-3-fluoro-phenyl) -6- [[2- (2-methoxy- 5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-7-yl] methyl] -2- thiazol- - carboxylate;
메틸 7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-2,5,6,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-카복실레이트;Methyl 7 - [[(4R) -4- (2-chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- -Yl] methyl] -3-oxo-2,5,6,8-tetrahydro-1H-imidazo [1,5-a] pyrazine-8a-carboxylate;
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(2-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(2-carboxy-phenyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin-7-ylmethyl] -4- (2- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-1,5,6,8-테트라하이드로이미다조[1,5-a]피라진-8a-일]아세트산;2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Dihydropyrimidin-6-yl] methyl] -2-cyclopropyl-3-oxo-1,5,6,8-tetrahydroimidazo [1,5-a] pyrazin-8-yl] acetic acid;
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-1,5,6,8-테트라하이드로이미다조[1,5-a]피라진-8a-일]아세트산;2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Dihydropyrimidin-6-yl] methyl] -2-isopropyl-3-oxo-1,5,6,8-tetrahydroimidazo [1,5-a] pyrazin-8-yl] acetic acid;
(R)-6-[(S)-2-(1-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-ylmethyl] -4 - (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
3-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산;4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carbonic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carbonic acid;
1-[[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;1 - [[(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid ;
1-[[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4 -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid ;
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산;Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro- Methyl-butanoic acid;
1-[[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-benzothiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopropanecarboxylic acid;
3-[(2S,8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로부탄카복실산;Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] cyclobutanecarboxylic acid;
3-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로부탄카복실산;4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] cyclobutanecarboxylic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid;
3-[(8aS)-7-[[(4S)-4-(3-플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3 - [(8aS) -7 - [[(4S) -4- (3-fluoro- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6- Yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산;2 - [(4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid;
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산;2 - [(4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid;
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산;2- [l- [(8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid;
(1R,2R)-2-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산;(2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid;
(1S,2R)-2-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산;(2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid;
(1R,2S)-2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산;(2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid;
(1S,2S)-2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산;(2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]부탄산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] butanoic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3,3-다이메틸-부탄산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
(R)-6-[(S)-2-(2-카복시-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(2-carboxy-ethyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin-7-ylmethyl] -4- (2- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-((R)-2-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-yl Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-((S)-2-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-yl Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6 - [(S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- 2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-((R)-2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Yl) methyl] -4 - ((R) - (S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- 2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-((1R,3S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(S) -2 - ((1R, 3S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- ] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-[(S)-2-((R)-(S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(S) -2 - ((R) - (S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Ylmethyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-((1R,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(S) -2 - ((1R, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [l, 5- a] pyrazin- ] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-[(S)-2-((1R,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(S) -2 - ((1R, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [l, 5- a] pyrazin- ] -4- (2-Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[2-(4-카복시-벤질)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;Ylmethyl] -4- (2-chloro-4- (4-fluoro-benzyl) -imidazo [1,5- a] pyrazin- Fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-[2-(4-카복시-벤질)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Ylmethyl] -4- (2-chloro-3- (4-fluorobenzyl) -3-oxo-hexahydro- Fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
2-[2-[7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]에톡시]아세트산;2- [7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] ethoxy] acetic acid;
2-[3-[7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]프로폭시]아세트산;2 - [(4R) -4- (2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] propoxy] acetic acid;
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[[2-(5-하이드록시-4,4-다이메틸-펜틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6- [ 8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-7-yl] methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-하이드록시에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Chloro-3-fluoro-phenyl) -6 - [[2- (2-hydroxyethyl) -Imidazo [1,5-a] pyrazin-7-yl] methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-하이드록시에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Chloro-3-fluoro-phenyl) -6 - [[2- (2-hydroxyethyl) -Imidazo [1,5-a] pyrazin-7-yl] methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] cyclohexanecarboxylic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] cyclohexanecarboxylic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3 - [(8aS) -7 - [[(4R) -4- (2-Chlorophenyl) -5-methoxycarbonyl-2-thiazol- -Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid;
2-[[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]부탄산;2 - [[(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] methyl] butanoic acid;
3-[(8aS)-7-[[(4S)-5-에톡시카본일-4-(3-플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;(3-fluoro-2-methyl-phenyl) -2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[4-(4-클로로페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;Yl] -1,4-dihydropyrimidin-6-yl] methyl] -1H-pyrazolo [3,4-d] pyrimidin- ] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메톡시-프로판산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Propanoic acid;
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]스피로[3.3]헵탄-6-카복실산;2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] spiro [3.3] heptane- 6-carboxylic acid;
5-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]펜탄산;5 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] pentanoic acid;
3-[[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로부탄카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4 Yl] methyl] cyclobutanecarboxylic acid < / RTI > < RTI ID = 0.0 &;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aS)-2-사이클로프로필-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -2-Cyclopropyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-2-사이클로프로필-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -2-Cyclopropyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4S) -4- (3,4-Difluoro-2-methyl-phenyl) -5-methoxycarbonyl- Yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4S) -4- (3,4-Difluoro- Yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8R,8aS)-2-t-부틸-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl (2S, -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aS)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aS)-2-t-부틸-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -2-t-Butyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5- methoxycarbonyl- Yl] -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carboxylic acid;
(8S,8aR)-2-t-부틸-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -2-t-Butyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carboxylic acid;
메틸 (8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-2,5,6,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-카복실레이트;Methyl (8aS) -7 - [[(4R) -4- (2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Pyrimidin-6-yl] methyl] -3-oxo-2,5,6,8-tetrahydro-1H-imidazo [1,5-a] pyrazine-8a-carboxylate;
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-1,1-다이메틸-3-옥소-6,8-다이하이드로-5H-옥사졸로[3,4-a]피라진-8a-일]아세트산;2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- 6-yl] methyl] -1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo [3,4-a] pyrazin-8-yl] acetic acid;
2-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-1,1-다이메틸-3-옥소-6,8-다이하이드로-5H-옥사졸로[3,4-a]피라진-8a-일]아세트산;2 - [(8aR) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- 6-yl] methyl] -1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo [3,4-a] pyrazin-8-yl] acetic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-메틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-메틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Methyl] -2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
메틸 (4R)-6-[[(8R,8aS)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(8R, 8aS) -2-t- butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8S,8aR)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(8S, 8aR) -2-t-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-프로폭시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3-fluoro-phenyl) -5-propoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산;Chloro-4-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
5-[7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]피리딘-2-카복실산;5- [7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] pyridine-2-carboxylic acid;
(S)-6-[(S)-2-(2-카복시-2,2-다이플루오로-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(S) -6- [(S) -2- (2-carboxy-2,2-difluoro-ethyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Methyl] -4- (3,4-difluoro-2-methyl-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; (8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-(4-메틸티아졸-2-일)-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;(3-fluoro-phenyl) -5-ethoxycarbonyl-2- (4-methylthiazol-2-yl) -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2,2-dimethyl-propanoic acid;
2-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-1-카복실산;2 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol- Yl] methyl] -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [1,2-a] pyrazine-1-carboxylic acid;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소부틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소부틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8R,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산;(8R, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid;
(8S,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산;(8S, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid;
에틸 (4R)-6-[[(8R,8aS)-2-t-부틸-8-(하이드록시메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; Ethyl (4R) -6 - [[(8R, 8aS) -2-t-butyl-8- (hydroxymethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ , 5- a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- Rate;
에틸 (4R)-6-[[(8S,8aR)-2-t-부틸-8-(하이드록시메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Ethyl (4R) -6 - [[(8S, 8aR) -2-t-butyl-8- (hydroxymethyl) -3-oxo-5,6,8,8a-tetrahydro- , 5- a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- Rate;
에틸 (4R)-6-[[(8aR)-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; (4R) -6- [[(8aR) -2-Isopropyl-3-oxo-5,6,8,8a-tetrahydro- 1 H- imidazo [1,5- a] pyrazin- Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
에틸 (4R)-6-[[(8aS)-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;(4R) -6- [[(8aS) -2-Isopropyl-3-oxo-5,6,8,8a-tetrahydro- IH- imidazo [1,5- a] pyrazin- Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid;
에틸 (4R)-6-[[(8aR)-2-(2-하이드록시-2-메틸-프로필)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; 또는Methyl-propyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1, 5-a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- ; or
에틸 (4R)-6-[[(8aS)-2-(2-하이드록시-2-메틸-프로필)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트.Methyl-propyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [l, 5-a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- .
본 발명의 더욱 특정한 화합물은 하기 화합물, 또는 이의 약학적으로 허용되는 염, 거울상이성질체 또는 부분입체이성질체이다:More particular compounds of the present invention are the following compounds, or pharmaceutically acceptable salts, enantiomers or diastereomers thereof:
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;Methyl-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid;
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산;3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carbonic acid;
1-[[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;1 - [[(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid ;
1-[[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4 -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid ;
1-[[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산;Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-benzothiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopropanecarboxylic acid;
3-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산; 4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3,3-다이메틸-부탄산;4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
(R)-6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터;(R) -6 - [(S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- 2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester;
6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-((R)-2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터;Yl) methyl] -4 - ((R) - (S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- 2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester;
3-[(8aS)-7-[[(4S)-5-에톡시카본일-4-(3-플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산;(3-fluoro-2-methyl-phenyl) -2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-2-사이클로프로필-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -2-Cyclopropyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4S) -4- (3,4-Difluoro- Yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl (2S, -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
(8S,8aR)-2-t-부틸-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -2-t-Butyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carboxylic acid;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-메틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Methyl] -2-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid;
메틸 (4R)-6-[[(8R,8aS)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; Methyl (4R) -6 - [[(8R, 8aS) -2-t- butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
메틸 (4R)-6-[[(8S,8aR)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트;Methyl (4R) -6 - [[(8S, 8aR) -2-t-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate;
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산;Chloro-4-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; (8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산;(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ;
2-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-1-카복실산;2 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol- Yl] methyl] -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [1,2-a] pyrazine-1-carboxylic acid;
(8R,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산; (8R, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid;
(8S,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산;(8S, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid;
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 또는(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid; or
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산.(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid.
합성synthesis
본 발명의 화합물은 임의의 통상적인 수단으로 제조될 수 있다. 이러한 화합물 뿐만 아니라 이의 출발 물질을 합성하기에 적합한 방법은 하기 반응식 및 실시예에 제공된다. 모든 치환기, 특히, R1 내지 R6, X, Y, W 및 n은 달리 나타내지 않는 한 상기 정의된 바와 같다. 또한, 달리 명확히 나타내지 않는 한, 모든 반응, 반응 조건, 약어 및 기호는 유기 화학 분야의 숙련자에게 널리 공지된 의미를 갖는다.The compounds of the present invention may be prepared by any conventional means. Suitable methods for synthesizing such compounds as well as their starting materials are provided in the following Schemes and Examples. All substituents, in particular R 1 to R 6 , X, Y, W and n are as defined above, unless otherwise indicated. Also, unless otherwise indicated, all reactions, reaction conditions, abbreviations, and symbols have well-known meaning to those skilled in the art of organic chemistry.
화합물 Ia에 대한 일반적인 합성 경로(반응식 1)The general synthetic route for compound Ia (Scheme 1)
[반응식 1][Reaction Scheme 1]
관심 화합물 Ia를 상기 반응식 1에 따라 제조할 수 있다. 아세틸 아세테이트 II, 벤즈알데하이드 III 및 티아졸 아미딘 IV 사이에 원-포트 반응시켜 다이하이드로피리미딘 V를 수득한다. 이어서, 상기 화합물 V를 SFC 키랄 분리하여 (-)-거울상이성질체 Va를 수득하고, 이의 입체화학을, 입체화학이 X-선 회절 연구에 의해 결정된 이의 특정한 화합물 B1 중 하나와 이의 SFC 체류 시간을 비교하여 측정한다(도 1). 화합물 Va를 브롬화하여 화합물 VI을 수득한다. 화합물 VI을 적합하게 융합된 아민 VII과 커플링하여 관심 화합물 Ia를 수득한다.The compound of interest Ia may be prepared according to scheme 1 above. The one-port reaction is carried out between acetyl acetate II , benzaldehyde III and thiazolamidine IV to give the dihydropyrimidine V. Subsequently, the compound V is subjected to SFC chiral separation to give the (-) - enantiomer Va , and its stereochemistry is compared with that of one of its specific compounds B1 whose stereochemistry is determined by X-ray diffraction study (Fig. 1). Compound Va is brominated to give compound VI . Compound VI is coupled with a suitably fused amine VII to yield the compound of interest Ia .
다이하이드로피리미딘 V를 아세틸 아세테이트 II, 알데하이드 III 및 티아졸 아미딘 IV의 순서로 축합 및 환화하여 제조할 수 있다. 상기 반응을 적합한 알코올성 용매, 예컨대 트라이플루오로에탄올 중에서 수 시간에 걸친 가열 조건하에 염기, 예컨대 칼륨 아세테이트의 존재하에 수행할 수 있다.Can be prepared by condensing and cyclizing the dihydropyrimidine V in the order of acetyl acetate II , aldehyde III and thiazolamidine IV . The reaction can be carried out in a suitable alcoholic solvent such as trifluoroethanol under heating conditions over several hours in the presence of a base such as potassium acetate.
화합물 V를 SFC 키랄 분리하여 (-)-거울상이성질체 Va를 수득한다.Compound V is SFC chiral cleaved to give (-) - enantiomer Va .
화합물 Va를 80 내지 100℃에서 적합한 불활성 용매, 예컨대 탄소 테트라클로라이드 중에서 브롬화제, 예컨대 N-브로모숙신이미드와 반응시켜 브로마이드 VI 을 제조할 수 있다.Compound Va may be reacted with a brominating agent such as N -bromosuccinimide in a suitable inert solvent such as carbon tetrachloride at 80-100 ° C to prepare bromide VI .
브로마이드 VI을 융합된 아민 VII과 커플링하여 관심 화합물 Ia를 수득할 수 있다. 상기 반응은 전형적으로 실온에서 수 시간에 걸쳐 적합한 용매, 예컨대 1,2-다이클로로에탄 중에서 유기 염기, 예컨대 N,N-다이이소프로필에틸아민의 존재하에 수행된다.Bromide VI can be coupled with the fused amine VII to give the compound of interest Ia . The reaction is typically carried out at room temperature over several hours in the presence of an organic base such as N , N -diisopropylethylamine in a suitable solvent such as 1,2-dichloroethane.
화합물 I의 부분입체이성질체 혼합물에 대한 일반적인 합성 경로(반응식 1-1)The general synthetic route to diastereomeric mixtures of compounds I (Scheme 1-1)
[반응식 1-1][Reaction Scheme 1-1]
관심 화합물 I을 다이하이드로피리미딘 V의 SFC 키랄 분리 없이 관심 화합물 Ia와 유사하게 제조할 수 있다.The compound of interest I can be prepared analogously to the compound of interest Ia without SFC chiral separation of the dihydropyrimidine V. [
반응식 1 또는 반응식 1-1에 대하여, 본 발명의 화학식 Ia, V, Va, Vb, VI, VI-1, I 및 임의의 다른 화합물의 2-티아졸릴 기는 C1-6알킬, 예컨대 메틸로 추가 치환될 수 있다.In Scheme 1 or Scheme 1-1, the 2-thiazolyl group of the compounds of formula Ia, V, Va, Vb, VI, VI-1, I and any other compound of the present invention is optionally substituted with C 1-6 alkyl, .
또한, 본 발명은 (a) 하기 화학식 VI-1의 화합물을 염기의 존재하에 하기 화학식 VII의 화합물과 반응시키는 단계를 포함하는, 본 발명의 화학식 I의 화합물 또는 다른 화합물의 제조 방법에 관한 것이다:The present invention also relates to a process for preparing a compound of formula (I) or another compound of the invention, which process comprises the steps of: (a) reacting a compound of formula (VI-1)
[화학식 VI-1][Formula VI-1]
[화학식 VII](VII)
상기 식에서,In this formula,
R1 내지 R6, X, Y, W 및 n은 달리 나타내지 않는 한 상기 정의된 바와 같다.R 1 to R 6 , X, Y, W and n are as defined above unless otherwise indicated.
단계 (a)에서, 염기는 예를 들면, N,N-다이이소프로필에틸아민일 수 있다.In step (a), the base may be, for example, N , N -diisopropylethylamine.
또한, 상기 방법에 따라 제조되는 본 발명의 화학식 I의 화합물 또는 다른 화합물은 본 발명의 목적이다.Also, the compounds of formula (I) or other compounds of the present invention prepared according to the above method are an object of the present invention.
약학 조성물 및 투여Pharmaceutical compositions and administration
본 발명은 또한 치료 활성 물질로서 사용하기 위한 본 발명의 화학식 I의 화합물 또는 다른 화합물에 관한 것이다.The invention also relates to compounds of formula (I) or other compounds of the invention for use as therapeutically active substances.
또 다른 실시양태는, 본 발명의 화합물 및 치료 불활성 담체, 희석제 또는 부형제를 함유하는 약학 조성물 또는 약제, 뿐만 아니라 상기 조성물 및 약제를 제조하기 위한 본 발명의 화합물의 사용 방법을 제공한다. 일 예에서, 본 발명의 화학식 I의 화합물 또는 다른 화합물은 주변 온도에서 적절한 pH에서 및 목적한 순도에서 생리학적으로 허용되는 담체, 즉, 생약 투여 형태로 이용되는 투여량 및 농도에서 수용자에게 무독성인 담체와 혼합하여 제형화될 수 있다. 제형의 pH는 주로 특정한 용도 및 화합물의 농도에 따르지만, 바람직하게는 약 3 내지 약 8의 범위이다. 일 예에서, 본 발명의 화학식 I의 화합물 또는 다른 화합물은 아세테이트 완충제(pH 5) 중에서 제형화된다. 또 다른 실시양태에서, 본 발명의 화학식 I의 화합물 및 다른 화합물은 멸균된다. 화합물은 예를 들면, 고체로서 또는 무정형 조성물로서, 동결건조된 제형으로서, 또는 수용액으로서 저장될 수 있다.Yet another embodiment provides a method of using the compounds of the invention for the manufacture of a pharmaceutical composition or medicament containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as the compositions and medicaments. In one example, the compounds of formula (I) or other compounds of the present invention are administered at a suitable pH and at the desired purity at ambient temperature to a physiologically acceptable carrier, i. E. And may be formulated by mixing with a carrier. The pH of the formulation depends primarily on the particular application and concentration of the compound, but is preferably in the range of from about 3 to about 8. In one example, compounds of formula I or other compounds of the invention are formulated in acetate buffer (pH 5). In another embodiment, the compounds of formula I and other compounds of the invention are sterile. The compound can be stored, for example, as a solid or as an amorphous composition, as a lyophilized formulation, or as an aqueous solution.
조성물은 우수한 의료 실시와 일치하는 방식으로 제형화되고, 복용되고, 투여된다. 이와 관련한 고려 인자는 치료될 특정한 질환, 치료될 특정한 인간, 개별 환자의 임상 조건, 질환의 원인, 약제의 전달 부위, 투여 방법, 투여 일정, 및 의사에게 공지된 다른 인자를 포함한다. 투여될 화합물의 "효과량"은 상기 고려에 의해 승인될 것이고, 혈청 HBV DNA 수준의 억제, HBeAb로의 HBeAg 혈청전환, 또는 HBeAg 손실, 또는 간 조직학에서 알라닌 아미노트랜스퍼라아제 수준의 정규화 및 개선에 필요한 최소량이다. 예를 들면, 상기 양은 정상 세포, 또는 전체로서 인간에게 독성인 양 미만일 수 있다.The compositions are formulated, dosed and administered in a manner consistent with good medical practice. Factors related to this include the particular disease to be treated, the particular human being to be treated, the clinical condition of the individual patient, the cause of the disease, the delivery site of the agent, the method of administration, the schedule of administration, and other factors known to the physician. The " effective amount " of the compound to be administered will be appreciated by the above considerations and will be necessary for the inhibition of serum HBV DNA levels, HBeAg serum conversion to HBeAb, or HBeAg loss, or normalization and improvement of alanine aminotransferase levels in liver histology It is the minimum amount. For example, the amount may be less than the amount that is toxic to normal cells, or to humans as a whole.
일 예에서, 투여량당 비경구로 투여된 본 발명의 화합물의 약학적 효과량은 약 0.01 내지 100 mg/환자 체중 kg/일, 다르게는 약 0.1 내지 20 mg/환자 체중 kg/일이고, 전형적으로 사용된 화합물의 초기 범위는 0.3 내지 15 mg/kg/일이다. 또 다른 실시양태에서, 경구 단위 투여 형태, 예컨대 정제 및 캡슐은 약 0.1 내지 약 1000 mg의 본 발명의 화합물을 함유한다.In one example, the pharmacologically effective amount of a compound of the invention administered parenterally per dose is from about 0.01 to 100 mg / kg body weight per day, alternatively from about 0.1 to 20 mg / patient body weight per day, Gt; mg / kg / day < / RTI > In another embodiment, oral dosage unit forms, such as tablets and capsules, contain from about 0.1 to about 1000 mg of a compound of the invention.
본 발명의 화합물은 임의의 적합한 수단에 의해, 예컨대, 경구, 국소(구강 및 설하를 포함함), 직장, 질, 경피, 비경구, 피하, 복강내, 폐내, 피부내, 척추강내 및 경막외, 및 비강내로 투여되고, 바람직한 경우, 국소 치료를 위해 병변내 투여될 수 있다. 비경구 주입은 근육내, 정맥내, 동맥내, 복강내 또는 피하 투여를 포함한다. The compounds of the present invention may be administered by any suitable means including, but not limited to, oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, , ≪ / RTI > and intranasally, and, if desired, can be administered in lesions for topical treatment. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.
본 발명의 화합물은 임의의 통상의 투여 형태, 예를 들면, 정제, 분말, 캡술, 용액, 분산액, 현탁액, 시럽, 스프레이, 좌제, 겔, 에멀젼, 패치 등으로 투여될 수 있다. 상기 조성물은 약학 제제 중 통상적인 구성성분, 예를 들면, 희석제, 담체, pH 조절제, 감미료, 증량제 및 추가 활성제를 함유할 수 있다.The compounds of the present invention may be administered in any conventional dosage form such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. The composition may contain conventional constituents in pharmaceutical preparations such as diluents, carriers, pH adjusting agents, sweeteners, extenders and additional active agents.
전형적인 제형은 본 발명의 화합물 및 담체 또는 부형제를 혼합하여 제조된다. 적합한 담체 및 부형제는 당업자에게 널리 공지되어 있고, 예를 들면, 문헌[Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004]; [Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000]; 및 [Rowe, Raymond C. Handbook of Pharmaceutical excipients. Chicago, Pharmaceutical Press, 2005]에 상세하게 기재되어 있다. 제형은 또한 하나 이상의 완충제, 안정화제, 계면활성제, 습윤제, 활택제, 유화제, 현탁제, 보존제, 항산화제, 불투명화제, 활주제, 가공보조제, 착색제, 감미료, 방향제, 풍미제, 희석제 및 약물(즉, 본 발명의 화합물 또는 이의 약학 조성물)의 우아한 제시를 제공하거나, 약학 생성물(즉, 약제)의 제조를 돕기 위한 다른 공제된 첨가제를 포함할 수 있다.Typical formulations are prepared by admixing the compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described, for example, in Ansel, Howard C., et al., Ansel ' s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004]; [Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000]; And Rowe, Raymond C. Handbook of Pharmaceutical excipients. Chicago, Pharmaceutical Press, 2005]. Formulations may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, bowels, processing aids, colorants, sweeteners, fragrances, flavors, (I. E., A compound of the invention or a pharmaceutical composition thereof), or other excipients to assist in the production of the pharmaceutical product (i. E., Pharmaceutical).
적합한 경구 투여 형태의 예는 약 30 mg 내지 90 mg의 무수 락토스, 약 5 mg 내지 40 mg의 나트륨 크로스카멜로스, 약 5 mg 내지 30 mg의 폴리비닐피롤리돈(PVP) K30, 및 약 1 mg 내지 10 mg의 마그네슘 스테아레이트와 함께 약 0.1 mg 내지 1000 mg의 본 발명의 화합물을 함유하는 정제이다. 분말화된 성분은 먼저 함께 혼합된 후 PVP의 용액과 혼합된다. 생성된 조성물은 건조되고 과립화되고 마그네슘 스테아레이트와 혼합되고 통상의 기기를 사용하여 정제 형태로 압축될 수 있다. 에어로졸 제형의 예는, 예를 들면 5 mg 내지 400 mg의, 본 발명의 화합물을 적합한 완충제 용액, 예를 들면, 포스페이트 완충제에 용해하고, 필요한 경우 긴장제, 예를 들면, 염, 예컨대 나트륨 클로라이드를 첨가하여 제조될 수 있다. 용액은, 예를 들면 0.2 μm 필터를 사용하여, 여과되어 불순물 및 오염물이 제거될 수 있다.Examples of suitable oral dosage forms include about 30 mg to 90 mg anhydrous lactose, about 5 mg to 40 mg sodium croscarmellose, about 5 mg to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 mg To about 10 mg of magnesium stearate together with about 0.1 mg to 1000 mg of the compound of the present invention. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition is dried, granulated and mixed with magnesium stearate and compressed into tablets using conventional equipment. Examples of aerosol formulations include, for example, from 5 mg to 400 mg of a compound of the invention in a suitable buffer solution such as phosphate buffer and, if necessary, a toning agent such as a salt such as sodium chloride . ≪ / RTI > The solution may be filtered, for example, using a 0.2 [mu] m filter to remove impurities and contaminants.
따라서, 일 실시양태는 화학식 I의 화합물, 또는 이의 입체이성질체 또는 약학적으로 허용되는 염을 포함하는 약학 조성물을 포함한다. 추가 실시양태에서는, 화학식 I의 화합물, 또는 이의 입체이성질체 또는 약학적으로 허용되는 염과 함께 약학적으로 허용되는 담체 또는 부형제를 포함하는 약학 조성물을 포함한다.Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof. In a further embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient together with a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
하기 실시예 A 및 B는 본 발명의 전형적인 조성물을 예시하지만, 단지 이의 대표로서 제공된다.The following Examples A and B illustrate typical compositions of the present invention, but are provided only as a representative thereof.
실시예 AExample A
본 발명의 화합물은 하기 조성의 정제의 생성을 위한 활성 성분으로서 그 자체로 공지된 방식으로 사용될 수 있다.The compounds of the present invention can be used in a manner known per se as the active ingredient for the production of tablets of the following composition.
실시예 BExample B
본 발명의 화합물은 하기 조성의 캡슐의 생성을 위한 활성 성분으로서 그 자체로 공지된 방식으로 사용될 수 있다.The compounds of the present invention can be used in a manner known per se as the active ingredient for the production of capsules of the following composition.
적응증 및 치료 방법 Indications and treatment methods
본 발명의 화합물은 HBV의 드노보 DNA 합성을 억제할 수 있고 HBV DNA 수준을 감소시킬 수 있다. 따라서, 본 발명의 화합물은 HBV 감염의 치료 또는 예방에 유용하다.The compounds of the present invention can inhibit de novo DNA synthesis of HBV and reduce HBV DNA levels. Accordingly, the compounds of the present invention are useful for the treatment or prevention of HBV infection.
본 발명의 화합물은 HBV 캡시드 억제제로서 유용하다.The compounds of the present invention are useful as HBV capside inhibitors.
본 발명은 HBV 감염의 치료 또는 예방을 위한 화학식 I의 화합물 또는 본 발명의 화합물의 용도에 관한 것이다.The present invention relates to the use of a compound of formula I or a compound of the invention for the treatment or prevention of HBV infection.
HBV 감염과 관련된 질병의 치료 또는 예방에 유용한 약제의 제조를 위한 화학식 I의 화합물 또는 본 발명의 화합물의 용도가 본 발명의 목적이다.The use of a compound of formula I or a compound of the invention for the manufacture of a medicament useful for the treatment or prevention of diseases associated with HBV infection is an object of the present invention.
본 발명은 특히 HBV 감염의 치료용 또는 예방용 약제의 제조를 위한 화학식 I의 화합물 또는 본 발명의 화합물의 용도에 관한 것이다.The invention relates in particular to the use of a compound of formula I or a compound of the invention for the manufacture of a medicament for the treatment or prevention of HBV infection.
또 다른 실시양태는 화학식 I의 화합물, 이의 입체이성질체, 호변이성질체, 전구약물 또는 약학적으로 허용되는 염을 효과량으로 투여하는 단계를 포함하는, HBV 감염의 치료 또는 예방 방법을 포함한다.Another embodiment includes a method of treating or preventing an HBV infection, comprising administering an effective amount of a compound of formula I, a stereoisomer, tautomer, prodrug, or pharmaceutically acceptable salt thereof.
조합 치료Combination therapy
본 발명의 화합물은 HBV의 치료 또는 예방을 위해 인터페론, 페길화된 인터페론, 라미부딘, 아데포비르 디피복실, 엔테카비르, 텔비부딘, 및 테노포비르 이소프록실과 함께 사용될 수 있다.The compounds of the present invention may be used in combination with interferon, pegylated interferon, lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir Isoproxil for the treatment or prevention of HBV.
실시예Example
본 발명은 하기 실시예를 참조하여 더욱 완전히 이해될 것이다. 그러나, 하기 실시예는 본 발명의 범주를 제한하는 것으로 간주되지 않아야 한다.The invention will be more fully understood by reference to the following examples. However, the following examples should not be construed as limiting the scope of the invention.
본원에 사용된 약어는 다음과 같다:Abbreviations used herein are as follows:
[α]D 20: 20℃에서 광학 회전[?] D 20 : Optical rotation at 20 ° C
BOMCl: 벤질클로로메틸 에스터BOMCl: benzyl chloromethyl ester
CC50: 세포의 50% 사멸을 야기하는 농도CC 50 : Concentration causing 50% cell death
CCK-8: 세포 카운팅 키트-8CCK - 8: Cell Counting Kit-8
CCl4: 탄소 테트라클로라이드CCl 4 : Carbon tetrachloride
Ct: 주기 역치Ct: Cycle Threshold
DIPEA: N,N-다이이소프로필에틸아민DIPEA: N, N -diisopropylethylamine
DCM: 다이클로로메틸렌DCM: dichloromethylene
PE: 석유 에터PE: Petroleum ether
DMSO: 다이메틸설폭사이드DMSO: dimethylsulfoxide
DEA: 다이에틸 아민DEA: diethylamine
DNA: 데옥시리보핵산DNA: deoxyribonucleic acid
EtOH: 에탄올EtOH: ethanol
EtOAc 또는 EA: 에틸 아세테이트EtOAc or EA: ethyl acetate
g: 그램g: gram
EC50: 최대 효과 반감 농도 EC 50 : maximum effect half-life
h, hr 또는 hrs: 시간h, hr, or hrs: hours
HAP: 헤테로아릴다이하이드로피리미딘HAP: Heteroaryl dihydropyrimidine
HATU: 1-[비스(다이메틸아미노)메틸렌]-1H-1,2,3-트라이아졸로[4,5-b]피리디늄 3-옥시드 헥사플루오로포스페이트HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
HBeAb: B형 간염 e 항체HBeAb: hepatitis B e antibody
HBeAg: B형 간염 e 항원HBeAg: hepatitis B e antigen
HBsAg: B형 간염 표면 항원HBsAg: Hepatitis B surface antigen
HCl: 수소 클로라이드HCl: hydrogen chloride
HPLC: 고성능 액체 크로마토그래피HPLC: High Performance Liquid Chromatography
HPLC-UV: 자외선 검출기를 갖는 고성능 액체 크로마토그래피HPLC-UV: High performance liquid chromatography with ultraviolet detector
Hz: 헤르츠Hz: Hertz
IPA: 이소프로판올IPA: isopropanol
LDA: 리튬 다이이소프로필아미드 LDA: Lithium diisopropylamide
메탄올-d4: 중수소화된 메탄올Methanol-d 4 : deuterated methanol
MeOH: 메탄올MeOH: methanol
mg: 밀리그램mg: milligrams
MHz: 메가헤르츠MHz: megahertz
min 또는 mins: 분min or mins: minutes
mL: 밀리리터mL: Milliliter
mm: 밀리미터mm: millimeter
mM: mmol/LmM: mmol / L
mmol: 밀리몰mmol: millimolar
MS: 질량 분석MS: mass spectrometry
MW: 분자량MW: molecular weight
Na2SO4: 나트륨 설페이트Na 2 SO 4 : Sodium sulfate
NaOH: 나트륨 하이드록사이드NaOH: sodium hydroxide
NBS: N-브로모숙신이미드NBS: N -bromosuccinimide
NMR: 핵 자기 공명NMR: nuclear magnetic resonance
PBS: 포스페이트 완충된 염수PBS: phosphate buffered saline
PD: 약역학PD: Pharmacokinetics
PK: 약동학PK: Pharmacokinetics
prep-HPLC: 제조용 고성능 액체 크로마토그래피prep-HPLC: High performance liquid chromatography for preparation
rt: 실온rt: room temperature
sat.: 포화됨sat .: saturated
SFC: 초임계 유체 크로마토그래피SFC: supercritical fluid chromatography
TEA: 트라이에틸아민TEA: Triethylamine
Tet: 테트라사이클린Tet: tetracycline
TFA: 트라이플루오로아세트산TFA: Trifluoroacetic acid
THF: 테트라하이드로푸란THF: tetrahydrofuran
μg: 마이크로그램μg: microgram
μL: 마이크로리터μL: microliter
μM: 마이크로몰μM: micro mol
UV: 자외선 검출기UV: ultraviolet detector
OD: 광학 밀도OD: optical density
pgRNA: 전구게놈 RNApgRNA: a precursor genomic RNA
qPCR: 정량 중합효소 연쇄 반응qPCR: Quantitative polymerase chain reaction
qRT-PCR: 정량 실시간 중합효소 연쇄 반응qRT-PCR: Quantitative real-time polymerase chain reaction
CYP: 시토크롬 P450CYP: Cytochrome P450
[Ir(COD)2Cl]2: 비스(1,5-사이클로옥타다이엔)다이이리듐(I)다이클로라이드[Ir (COD) 2 Cl] 2 : bis (1,5-cyclooctadiene) diaridium (I) dichloride
Cs2CO3: 세슘 카보네이트Cs 2 CO 3 : Cesium carbonate
Pd(OAc)2: 팔라듐(II) 아세테이트Pd (OAc) 2 : Palladium (II) acetate
NaBH4: 나트륨 보로하이드라이드NaBH 4 : Sodium borohydride
RuCl3: 루테늄(III) 클로라이드RuCl 3 : ruthenium (III) chloride
일반적인 실험 조건General experimental conditions
중간체 및 최종 화합물을 하기 기계 중 하나를 사용하여 플래시 크로마토그래피로 정제하였다: i) 바이오타지(Biotage) SP1 시스템 및 쿼드(Quad) 12/25 카트리지 모듈. ii) ISCO 콤비-플래시 크로마토그래피 기계. 실리카 겔 브랜드 및 공극 크기: i) KP-SIL 60 Å, 입자 크기: 40 내지 60 μM; ii) CAS 등록번호 실리카 겔: 63231-67-4, 입자 크기: 47 내지 60 μm 실리카 겔; iii) 칭다오 하이양 케미칼 캄파니 리미티드(Qingdao Haiyang Chemical Co., Ltd)로부터의 ZCX, 공극: 200 내지 300, 또는 300 내지 400. The intermediate and final compound were purified by flash chromatography using one of the following machines: i) Biotage SP1 system and Quad 12/25 cartridge module. ii) ISCO combi-flash chromatography machine. Silica gel brand and pore size: i) KP-SIL 60 A, particle size: 40-60 uM; ii) CAS Registration Number Silica gel: 63231-67-4, particle size: 47-60 占 퐉 silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pores: 200-300, or 300-400.
중간체 및 최종 화합물을 XBridge(상표) Prep-C18(5 μm, OBDTM 30 x 100 mm) 컬럼 또는 선파이어(SunFire: 상표) Prep-C18(5 μm, OBDTM 30 x 100 mm) 컬럼을 사용하여 역상 컬럼에서 제조용 HPLC로 정제하였다. 워터스 오토피(Waters AutoP) 정제 시스템(컬럼: XBridge(상표) Prep-C18, 30 x 100 mm, 샘플 매니저 2767, 펌프 2525, 검출기: 마이크로매스(Micromass) ZQ 및 UV 2487, 용매 시스템: 물 중 아세토니트릴 및 0.1% 암모늄 하이드록사이드). SFC 키랄 분리를 위해, 중간체를 메틀러 톨레도(Mettler Toledo) SFC-멀티그램 III 시스템, 용매 시스템: 95% CO2 및 5% IPA(IPA 중 0.5% TEA), 배압 100 바, 254 nm에서 UV 검출을 사용하여 키랄 컬럼(다이셀 키랄팩(Daicel Chiralpak) IC, 5 μm, 30 x 250 mm)으로 분리하였다. The intermediate and final compound were purified by reverse phase column chromatography using an XBridge (TM) Prep-C18 (5 [mu] m, OBDTM 30 x 100 mm) column or SunFire (TM) Prep- Lt; / RTI > for purification by preparative HPLC. Waters AutoP purification system (column: XBridge (TM) Prep-C18, 30 x 100 mm, sample manager 2767, pump 2525, detector: Micromass ZQ and UV 2487, solvent system: acetone in water Nitrile and 0.1% ammonium hydroxide). For SFC chiral separation, the intermediate was detected with UV detection at 254 nm, Mettler Toledo SFC-Multigram III system, solvent system: 95% CO 2 and 5% IPA (0.5% TEA in IPA) (Daicel Chiralpak IC, 5 [mu] m, 30 x 250 mm).
화합물의 LC/MS 스펙트럼은 LC/MS(워터스(상표) 알리안스(Alliance) 2795-마이크로매스 ZQ)를 사용하여 수득하고, LC/MS 조건은 다음과 같다(실행 시간 6 분):The LC / MS spectra of the compounds were obtained using LC / MS (Waters (Alliance) 2795-Micromass ZQ) and LC / MS conditions were as follows (run time 6 min):
산성 조건: A: H2O 중 0.1% 포름산; B: 아세토니트릴 중 0.1% 포름산;Acidic conditions: A: 0.1% formic acid in H 2 O; B: 0.1% formic acid in acetonitrile;
염기성 조건: A: H2O 중 0.1% NH3ㆍH2O; B: 아세토니트릴;Basic conditions: A: H 2 O of 0.1% NH 3 and H 2 O; B: acetonitrile;
중성 조건: A: H2O; B: 아세토니트릴.Neutral conditions: A: H 2 O; B: Acetonitrile.
질량 스펙트럼(MS): 일반적으로 모 질량을 나타내는 이온만이 보고되었고, 달리 언급하지 않는 한, 인용된 질량 이온은 양성 질량 이온(MH)+이다.Mass spectrum (MS): Only ions that generally show a mass are reported, and unless quoted otherwise, the quoted mass ion is a positive mass ion (MH) + .
브루커 애반스(Bruker Avance) 400 MHz를 사용하여 NMR 스펙트럼을 수득하였다.NMR spectra were obtained using a Bruker Avance 400 MHz.
단일 결정을 루프에 장착하고 질소 스트림에서 160 K로 냉각하였다. 데이타를 Cu-K-알파-방사선(1.54178 Å)을 갖는 게미니 알 울트라(Gemini R Ultra) 회절계(옥스포드 디프랙션(Oxford Diffraction), 영국 소재)로 수집하고, 크리살리스-패키지(Crysalis-package)로 처리하였다. ShelXTL 소프트웨어(브루커 에이엑스에스(Bruker AXS), 독일 칼스루에 소재)를 사용하여 구조 해결 및 개선을 수행하였다.A single crystal was mounted in the loop and cooled to 160 K in a nitrogen stream. Data were collected with a Gemini R Ultra diffractometer (Oxford Diffraction, UK) with Cu-K-alpha-radiation (1.54178 A) and analyzed using a Crysalis- -package). Structural solutions and improvements were performed using ShelXTL software (Bruker AXS, Karlsruhe, Germany).
마이크파 지원된 반응을 바이오타지 이니시에이터 식스티(Biotage Initiator Sixty) 마이크로파 합성기로 수행하였다.Microwave assisted reactions were performed with a Biotage Initiator Sixty microwave synthesizer.
공기-민감성 시약을 수반하는 모든 반응을 아르곤 대기하에 수행하였다. 달리 나타내지 않는 한 시약을 추가 정제 없이 통상의 공급처로부터 받은 그대로 사용하였다.All reactions involving air-sensitive reagents were performed under an argon atmosphere. Unless otherwise indicated, the reagents were used as received from a conventional source without further purification.
제조예Manufacturing example
본 발명은 하기 실시예를 참조하여 더욱 완전히 이해될 것이다. 그러나, 실시예는 본 발명의 범주를 제한하는 것으로서 간주되지 않아야 한다.The invention will be more fully understood by reference to the following examples. However, the embodiments should not be construed as limiting the scope of the present invention.
실시예 1Example 1
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,8,9,9a-헥사하이드로피라지노[1,2-c][1,3]옥사진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(6-oxo-1,3,4,8,9,9a-hexahydropyrazino [ ] [1,3] oxazin-2-yl) methyl] -2-thiazol-2-yl-1,4- dihydropyrimidine-
반응식 1에 나타낸 일반적인 합성 경로에 따라 표제 화합물을 제조하였다. 상세한 합성 경로를 하기 반응식 2에 제공하였다.The title compound was prepared according to the general synthetic route shown in Scheme 1. A detailed synthetic route is provided in Scheme 2 below.
[반응식 2][Reaction Scheme 2]
화합물 A의 제조Preparation of Compound A
무수 MeOH(5 mL) 중 티아졸-2-카보니트릴(1.5 g, 14 mmol)의 교반된 용액에 무수 메탄올(10 mL) 중 나트륨 메톡사이드(0.74 g, 14 mmol)의 용액을 적가하였다. 반응 혼합물을 실온에서 출발 물질이 사라질 때까지 교반하였다. 그 후, 암모늄 클로라이드(1.5 g, 28 mmol)를 한번에 첨가하고, 반응 혼합물을 밤새 교반하였다. 용해되지 않은 물질을 여과로 제거하고, 여액을 농축하여 회색 고체로서 티아졸-2-카복스아미딘 하이드로클로라이드(화합물 A)를 수득하고, 이를 추가 정제 없이 다음 단계에서 직접 사용하였다. MS: 계산치 128(MH+), 측정치 128(MH+).To a stirred solution of thiazole-2-carbonitrile (1.5 g, 14 mmol) in anhydrous MeOH (5 mL) was added dropwise a solution of sodium methoxide (0.74 g, 14 mmol) in anhydrous methanol (10 mL). The reaction mixture was stirred at room temperature until the starting material disappeared. Ammonium chloride (1.5 g, 28 mmol) was then added in one portion and the reaction mixture was stirred overnight. The undissolved material was removed by filtration and the filtrate was concentrated to give thiazole-2-carboxamidine hydrochloride (Compound A) as a gray solid which was used directly in the next step without further purification. MS: Calcd. 128 (MH + ), Measurement 128 (MH + ).
화합물 B의 제조Preparation of Compound B
트라이플루오로에탄올(8 mL) 중 티아졸-2-카복스아미딘 하이드로클로라이드(0.13 g, 1.0 mmol), 메틸 아세토아세테이트(0.12 g, 1.0 mmol) 및 2-클로로-4-플루오로벤즈알데하이드(0.16 g, 1.0 mmol)의 교반된 용액에 칼륨 아세테이트(0.20 g, 2.0 mmol)를 첨가하였다. 반응 혼합물을 16 시간 동안 환류하였다. 이를 실온으로 냉각한 후, 반응 혼합물을 농축하고, 잔사를 에틸 아세테이트에 용해한 후 염수로 세척하였다. 유기 층을 나트륨 설페이트로 건조하였다. 용매를 농축하고, 잔사를 컬럼 크로마토그래피(에틸 아세테이트/석유 에터는 1/4로부터 1/2이다)로 정제하여 황색 고체로서 4-(2-클로로-4-플루오로-페닐)-6-메틸-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 B)를 수득하였다. MS: 계산치(MH+) 366, 측정치(MH+) 366.To a solution of thiazole-2-carboxamidine hydrochloride (0.13 g, 1.0 mmol), methyl acetoacetate (0.12 g, 1.0 mmol) and 2-chloro-4-fluorobenzaldehyde ( 0.16 g, 1.0 mmol) in THF (20 mL) was added potassium acetate (0.20 g, 2.0 mmol). The reaction mixture was refluxed for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate. The solvent was concentrated and the residue was purified by column chromatography (ethyl acetate / petroleum ether 1/4 to 1/2) to give 4- (2-chloro-4-fluoro-phenyl) Thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B). MS: calculated (MH + ) 366, found (MH + ) 366.
화합물 B1의 제조Preparation of Compound B1
4-(2-클로로-4-플루오로-페닐)-6-메틸-2-옥사졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 B)를 100 mL/분의 속도로 85% 초임계 CO2/15% EtOH의 혼합된 용매로 용리하는 SFC(SFC-멀티그램; IC: 5 x 250 mm, 5μ) 키랄 분리하여 거울상이성질체 (R)-4-(2-클로로-4-플루오로-페닐)-6-메틸-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 B1)를 수득하였다. 목적한 (-)-거울상이성질체(B1)를 (+)-거울상이성질체(B2) 이전에 용리하였다. (-)-거울상이성질체(B1)의 절대 배열을 X-선 회절 연구로 측정하였다(도 1).Methyl-2-oxazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (Compound B) was chiral separation of the SFC (SFC-multigram; IC: 5 x 250 mm, 5μ) eluting with a mixed solvent of 85% supercritical CO 2 /15% EtOH at a rate of 100 mL / min to give the enantiomer (R Yl) -l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester (compound B1). The desired (-) - enantiomer (B1) was eluted before the (+) - enantiomer (B2). The absolute arrangement of the (-) - enantiomer (B1) was determined by X-ray diffraction studies (Fig. 1).
화합물 B1: [α]D 20 -55.0(c 0.845, MeOH). Compound B1 : [?] D 20 -55.0 (c 0.845, MeOH).
화합물 B2: [α]D 20 +44.6(c 0.175, MeOH). Compound B2 : [?] D 20 +44.6 (c 0.175, MeOH).
화합물 C의 제조Preparation of Compound C
CCl4(5 mL) 중 (R)-4-(2-클로로-4-플루오로-페닐)-6-메틸-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(0.37 g, 1.0 mmol)의 교반된 용액에 NBS(0.20 g, 1.1 mmol)를 한번에 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하고, 잔사를 컬럼 크로마토그래피로 정제하여 황색 고체로서 (R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C)를 수득하였다. MS: 계산치 445(MH+), 측정치 445(MH+).CCl 4 (5 mL) of (R) -4- (2- chloro-4-fluoro-phenyl) -6-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidin -5 -Carboxylic acid methyl ester (0.37 g, 1.0 mmol) in N, N-dimethylformamide (1 mL) was added NBS (0.20 g, 1.1 mmol) in one portion. The reaction mixture was stirred at room temperature for 1 hour, then the solvent was removed in vacuo and the residue was purified by column chromatography to give ( R ) -6-bromomethyl-4- (2-chloro-4- Phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester C). MS: Calcd. 445 (MH + ), Measurement 445 (MH + ).
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D)의 제조Hexahydro-pyrazino [l, 2-c] [1,3] oxazin-6-one (Compound D)
단계 1: 메틸 4-boc-피페라진-2-아세테이트(CAS 번호: 183742-33-8, 켐파인더(Chemfinder))(1.0 g, 4 mmol)를 MeOH(10 mL)에 용해한 후, NaBH4(1.5 g, 40 mmol)를 적가하고, 밤새 교반하였다. 용매를 진공에서 제거하고, 잔사를 EtOAc와 물 사이에 분배하였다. 유기 층을 분리하고, 이어서 Na2SO4로 건조하고, 농축하여 조질 오일로서 3-(2-하이드록시-에틸)-피페라진-1-카복실산 t-부틸 에스터(화합물 E)를 수득하고, 이를 추가 정제 없이 직접 사용하였다. Step 1: methyl 4-boc- piperazine-2-acetate was dissolved in (CAS No. 183742-33-8, Chem finder (Chemfinder)) (1.0 g, 4 mmol) to MeOH (10 mL), NaBH 4 ( 1.5 g, 40 mmol) was added dropwise and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc and water. The organic layer was separated and then dried over Na 2 SO 4 and concentrated to give 3- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid tert - butyl ester (Compound E) as a crude oil, Used directly without further purification.
단계 2: 3-(2-하이드록시-에틸)-피페라진-1-카복실산 t-부틸 에스터(58 mg, 0.25 mmol)를 다이클로로메탄(4 mL) 및 DIPEA(1 mL)에 용해한 후, 트라이포스겐(27 mg, 0.09 mmol)을 실온에서 첨가하였다. 반응 혼합물을 30 분 동안 교반하고, 용매를 진공에서 제거하였다. 잔사를 다이클로로메탄(3 mL) 및 TFA(1 mL)에 용해하였다. 반응 혼합물을 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물로서 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온 트라이플루오로 아세트산 염(화합물 D)을 수득하고, 이를 추가 정제 없이 직접 사용하였다. LC/MS: 계산치 157(MH+), 측정치 157(MH+). Step 2: 3- (2-Hydroxy-ethyl) -piperazine-l-carboxylic acid tert - butyl ester (58 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL) and DIPEA (1 mL) Phosgene (27 mg, 0.09 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (3 mL) and TFA (1 mL). The reaction mixture was stirred for 1 hour and then the solvent was removed in vacuo to give hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one trifluoroacetic acid salt (compound D ) Which was used directly without further purification. LC / MS: calculated 157 (MH + ), found 157 (MH + ).
실시예 1의 제조Preparation of Example 1
1,2-다이클로로에탄(5 mL) 중 (R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(0.072 g, 0.16 mmol) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온 트라이플루오로 아세트산 염(화합물 D, 조질, 0.25 mmol)의 교반된 용액에 DIPEA(0.078 mL, 0.45 mmol)를 적가하였다. 반응 혼합물을 실온에서 출발 물질이 사라질 때까지 교반하였다. 혼합물을 EtOAc(50 mL)로 희석하고, 포화 NH4Cl 수용액 및 염수로 연속적으로 세척하였다. 유기 층을 분리한 후 Na2SO4로 건조하였다. 용매를 진공에서 농축하고, 조질 생성물을 prep-HPLC로 정제하여 연황색 고체로서 메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,8,9,9a-헥사하이드로피라지노[1,2-c][1,3]옥사진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(실시예 1)(11 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(dd, J = 3.01, 1.00 Hz, 1H), 7.81(d, J = 3.01 Hz, 1H), 7.46(dd, J = 8.66, 6.15 Hz, 1H), 7.26(dd, J = 8.78, 2.51 Hz, 1H), 7.00-7.13(m, 1H), 6.19(d, J = 1.76 Hz, 1H), 4.19-4.48(m, 4H), 4.11(d, J = 16.06 Hz, 1H), 3.76-3.94(m, 1H), 3.62(s, 3H), 3.18-3.31(m, 2H), 2.37-2.80(m, 3H), 2.11-2.30(m, 1H), 1.90(qdd, J = 14.37, 14.37, 14.37, 9.22, 5.40 Hz, 1H). MS: 계산치 520(MH+), 측정치 520(MH+).To a solution of ( R ) -6-bromomethyl-4- (2-chloro-4-fluoro-phenyl) -2-thiazol- Dihydro-pyrimidine-5-carboxylic acid methyl ester (0.072 g, 0.16 mmol) and hexahydro-pyrazino [1,2- c] [1,3] oxazin-6-one trifluoroacetic acid salt (compound D , Crude, 0.25 mmol) in THF (5 mL) was added dropwise DIPEA (0.078 mL, 0.45 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared. The mixture was diluted with EtOAc (50 mL), washed successively with saturated aqueous NH 4 Cl and brine. The organic layer was separated and dried over Na 2 SO 4 . The solvent was concentrated in vacuo and the crude product purified by prep-HPLC to give methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6- [ Yl) methyl] -2-thiazol-2-yl-l, 4-di 5-carboxylate (example 1) (11 mg). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (dd , J = 3.01, 1.00 Hz, 1H), 7.81 (d, J = 3.01 Hz, 1H), 7.46 (dd, J = 8.66, 6.15 Hz (M, 1H), 7.26 (dd , J = 8.78, 2.51 Hz, 1H), 7.00-7.13 (m, 1H), 6.19 (d , J = 1.76 Hz, 1H), 4.19-4.48 d, J = 16.06 Hz, 1H ), 3.76-3.94 (m, 1H), 3.62 (s, 3H), 3.18-3.31 (m, 2H), 2.37-2.80 (m, 3H), 2.11-2.30 (m, 1H), 1.90 (qdd , J = 14.37, 14.37, 14.37, 9.22, 5.40 Hz, 1H). MS: Calcd. 520 (MH + ), found 520 (MH + ).
실시예 2Example 2
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(4-옥소-6,7,9,9a-테트라하이드로-1H-피라지노[2,1-c][1,4]옥사진-8-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(4-fluoro-phenyl) -6 - [(4-oxo-6,7,9,9a-tetrahydro-1H-pyrazino [ Yl] methyl] -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 1,6,7,8,9,9a-헥사하이드로피라지노[2,1-c][1,4]옥사진-4-온(우씨 앱테크(우한) 캄파니 리미티드(WuXi AppTec(Wuhan) Co., Ltd), 카탈로그 번호: WX111240; 이의 합성을 위해, 탕(Tang Pengcho) 등의 PCT 국제 출원 WO 2012/019426을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 2(9 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.14 Hz, 1H), 7.76(d, J = 3.14 Hz, 1H), 7.43(dd, J = 8.72, 6.09 Hz, 1H), 7.24(dd, J = 8.72, 2.57 Hz, 1H), 6.96-7.12(m, 1H), 6.18(d, J = 2.26 Hz, 1H), 4.46-4.66(m, 1H), 4.05-4.22(m, 3H), 3.77-4.05(m, 3H), 3.53-3.73(m, 4H), 2.94-3.13(m, 2H), 2.81-2.94(m, 1H), 2.15-2.52(m, 2H). MS: 계산치 520(MH+), 측정치 520(MH+).Hexahydro-pyrazino [l, 2-c] [1,3] oxazin-6-one (compound D) c] [1,4] oxazin-4-one (WuXi AppTec (Wuhan) Co., Ltd), catalog number: WX111240; Tang Pengcho , ≪ / RTI > PCT international application WO < RTI ID = 0.0 > 2012/019426). ≪ / RTI > Example 2 (9 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.14 Hz, 1H), 7.76 (d, J = 3.14 Hz, 1H), 7.43 (dd, J = 8.72, 6.09 Hz, 1H ), 7.24 (dd , J = 8.72,2.57 Hz, 1H), 6.96-7.12 (m, 1H), 6.18 (d , J = 2.26 Hz, 1H), 4.46-4.66 m, 3H), 3.77-4.05 (m, 3H), 3.53-3.73 (m, 4H), 2.94-3.13 (m, 2H), 2.81-2.94 (m, 1H), 2.15-2.52 (m, 2H). MS: Calcd. 520 (MH + ), found 520 (MH + ).
실시예 3Example 3
메틸 (4R)-6-[[(8aR)-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl] -4-methyl-4H-pyrrolo [2,3-c] pyridazin- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-
3-(2-하이드록시-에틸)-피페라진-1-카복실산 t-부틸 에스터(화합물 E) 대신에 (S)-4-N-Boc-2-하이드록시메틸-피페라진(CAS 번호: 314741-40-7, 베팜(Bepharm))을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 3(21 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.93-8.00(m, 1H), 7.73-7.84(m, 1H), 7.40-7.50(m, 1H), 7.25(dd, J = 8.66, 2.64 Hz, 1H), 7.00-7.12(m, 1H), 6.15-6.22(m, 1H), 4.42-4.57(m, 1H), 4.25(d, J = 16.81 Hz, 1H), 4.13-4.22(m, 1H), 3.99-4.13(m, 2H), 3.78-3.90(m, 1H), 3.56-3.67(m, 3H), 3.29-3.39(m, 1H), 3.25(d, J = 9.03 Hz, 1H), 2.96(d, J = 11.04 Hz, 1H), 2.30-2.61(m, 2H). MS: 계산치 506(MH+), 측정치 506(MH+).3- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid t- butyl ester (compound E) in place of (S) -4- N -Boc-2-hydroxy-2-methyl-piperazine (CAS number: 314 741 -40-7, Bepharm), the title compound was prepared. Example 3 (21 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.93-8.00 (m , 1H), 7.73-7.84 (m, 1H), 7.40-7.50 (m, 1H), 7.25 (dd, J = 8.66, 2.64 (M, 1H), 4.25 (d , J = 16.81 Hz, 1H), 4.13-4.22 (m, 1H), 3.99-4.13 (m, 2H ), 3.78-3.90 (m, 1H), 3.56-3.67 (m, 3H), 3.29-3.39 (m, 1H), 3.25 (d, J = 9.03 Hz, 1H) , 2.96 (d , J = 11.04 Hz, 1H), 2.30-2.61 (m, 2H). MS: Calc 506 (MH + ), found 506 (MH + ).
실시예 4Example 4
메틸 (4R)-6-[[(8aS)-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl] methyl] -4- (4-trifluoromethyl-pyrimidin-4-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-
3-(2-하이드록시-에틸)-피페라진-1-카복실산 t-부틸 에스터(화합물 E) 대신에 (R)-4-N-boc-2-하이드록시메틸-피페라진(CAS 번호: 278788-66-2, 베팜)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 4(20 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.92-8.00(m, 1H), 7.78(d, J = 3.26 Hz, 1H), 7.44(dd, J = 8.78, 6.02 Hz, 1H), 7.25(dd, J = 8.66, 2.64 Hz, 1H), 7.01-7.12(m, 1H), 6.14-6.21(m, 1H), 4.46(t, J = 8.53 Hz, 1H), 4.18-4.26(m, 1H), 4.08-4.18(m, 1H), 3.97-4.08(m, 2H), 3.82-3.93(m, 1H), 3.53-3.67(m, 3H), 3.34-3.40(m, 1H), 3.08(d, J = 10.54 Hz, 2H), 2.46-2.60(m, 1H), 2.28-2.44(m, 1H). MS: 계산치 506(MH+), 측정치 506(MH+).3- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid t- butyl ester (compound E) in place of (R) -4-N-boc-2-hydroxymethyl-piperazine (CAS number: 278 788 -66-2, Befam), the title compound was prepared. Example 4 (20 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.92-8.00 (m , 1H), 7.78 (d, J = 3.26 Hz, 1H), 7.44 (dd, J = 8.78, 6.02 Hz, 1H), 7.25 (d , J = 8.66, 2.64 Hz, 1H), 7.01-7.12 (m, 1H), 6.14-6.21 (m, 1H), 4.46 (t , J = 8.53 Hz, 1H), 4.18-4.26 ), 4.08-4.18 (m, 1H), 3.97-4.08 (m, 2H), 3.82-3.93 (m, 1H), 3.53-3.67 , J = 10.54 Hz, 2H), 2.46-2.60 (m, 1H), 2.28-2.44 (m, 1H). MS: Calc 506 (MH + ), found 506 (MH + ).
실시예 5Example 5
메틸 (4R)-6-[[(8aS)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl] methyl] -4 (4H) -6- [[(8aS) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-chloro-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 F)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 연황색 고체로서 실시예 5(14 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.90-7.99(m, 1H), 7.72-7.82(m, 1H), 7.36-7.52(m, 1H), 7.20-7.31(m, 1H), 7.06(td, J = 8.41, 2.76 Hz, 1H), 6.18(s, 1H), 4.18(d, J = 17.07 Hz, 1H), 3.97-4.04(m, 2H), 3.86-3.97(m, 1H), 3.61(s, 3H), 3.21(d, J = 9.29 Hz, 1H), 3.03-3.16(m, 1H), 2.83-2.95(m, 1H), 2.36-2.56(m, 2H), 2.19-2.35(m, 3H), 1.66-1.82(m, 1H). MS: 계산치 504(MH+), 측정치 504(MH+).Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ ] Pyrazin-2-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound F) was SFC chiral separation. Example 5 (14 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.90-7.99 (m , 1H), 7.72-7.82 (m, 1H), 7.36-7.52 (m, 1H), 7.20-7.31 (m, 1H), 7.06 (td, J = 8.41, 2.76 Hz, 1H), 6.18 (s, 1H), 4.18 (d, J = 17.07 Hz, 1H), 3.97-4.04 (m, 2H), 3.86-3.97 (m, 1H) , 3.61 (s, 3H), 3.21 (d , J = 9.29 Hz, IH), 3.03-3.16 (m, IH), 2.83-2.95 (m, (m, 3 H), 1.66 - 1.82 (m, 1 H). MS: Calc 504 (MH + ), found 504 (MH + ).
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 F)의 제조Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ ] Pyrazin-2-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound F)
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 헥사하이드로피롤로[1,2-a]피라진-6(2H)-온(CAS 번호: 117810-52-3, 베팜; 이의 합성을 위해, 알바로(Alvaro G.) 및 라지(Large C.)의 PCT 국제 출원 WO 2008/090115를 참조한다)을 사용하여 실시예 1과 유사하게 화합물 F를 제조하였다.1,2-a] pyrazin-6 (2H) -one (CAS (Compound C) instead of hexahydro- pyrazino [1,2- c] [1,3] oxazin- No. 117810-52-3, Behemam; for synthesis thereof, see Alvaro G. and Large C., PCT International Application WO 2008/090115) Compound F was prepared.
실시예 6Example 6
메틸 (4R)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl] methyl] -4 (4H) -6- [[(8aR) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-chloro-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
실시예 5의 메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 F)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 연황색 고체로서 실시예 6(14 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.87-8.01(m, 1H), 7.71-7.81(m, 1H), 7.36-7.49(m, 1H), 7.19-7.29(m, 1H), 7.06(td, J = 8.41, 2.51 Hz, 1H), 6.18(s, 1H), 4.11-4.21(m, 1H), 4.06(dd, J = 12.55, 3.01 Hz, 1H), 3.95-4.02(m, 1H), 3.89(dtd, J = 10.73, 7.25, 7.25, 3.64 Hz, 1H), 3.53-3.65(m, 3H), 3.01-3.19(m, 3H), 2.33-2.54(m, 3H), 2.22(dddd, J = 13.08, 9.38, 7.65, 4.02 Hz, 1H), 2.12(t, J = 10.92 Hz, 1H), 1.61-1.76(m, 1H). MS: 계산치 504(MH+), 측정치 504(MH+).(4R) -4- (2-Chloro-4-fluoro-phenyl) -6 - [(6-oxo- l, 3,4,7,8,8a-hexahydropyrrolo [ 2-yl] -1,4-dihydropyrimidine-5-carboxylate (Compound F) was separated by SFC chiral separation to give the title compound . Example 6 (14 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.87-8.01 (m , 1H), 7.71-7.81 (m, 1H), 7.36-7.49 (m, 1H), 7.19-7.29 (m, 1H), (Dd , J = 12.55, 3.01 Hz, 1H), 3.95-4.02 (m, 1H), 7.06 (td , J = 8.41, 2.51 Hz, (M, 3H), 2.33-2.54 (m, 3H), 2.22 (m, 1H), 3.89 (ddt , J = 10.73, 7.25, 7.25, (d , 1H, dddd, J = 13.08, 9.38, 7.65, 4.02 Hz, 1H), 2.12 (t , J = 10.92 Hz, 1H), 1.61-1.76 (m, MS: Calc 504 (MH + ), found 504 (MH + ).
실시예 7Example 7
메틸 (4R)-6-[[(8aR)-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl] -4-methyl-4H-pyrrolo [2,3-c] pyridazin- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-
2-클로로-4-플루오로벤즈알데하이드 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-브로모-4-플루오로벤즈알데하이드 및 (8aR)-2,3,4,7,8,8a-헥사하이드로-1H-피롤로[1,2-a]피라진-6-온(이의 합성을 위해, 탕 등의 PCT 국제 출원 WO 2012/019426을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 7(19 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.26 Hz, 1H), 7.76(d, J = 3.01 Hz, 1H), 7.35-7.48(m, 2H), 7.11(td, J = 8.41, 2.76 Hz, 1H), 6.17(s, 1H), 4.09-4.19(m, 1H), 4.05(dd, J = 12.80, 2.76 Hz, 1H), 3.93-4.01(m, 1H), 3.89(dtd, J = 10.63, 7.23, 7.23, 3.76 Hz, 1H), 3.61(s, 3H), 2.95-3.18(m, 3H), 2.31-2.54(m, 3H), 2.15-2.28(m, 1H), 2.08(t, J = 10.92 Hz, 1H), 1.61-1.75(m, 1H). MS: 계산치 548(MH+), 측정치 548(MH+).Bromo-4-fluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde and hexahydro-pyrazino [1,2-c] [1,3] oxazin- 6-one (for the synthesis of which is described in PCT international application WO < RTI ID = 0.0 > The title compound was prepared in analogy to example 1, Example 7 (19 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.26 Hz, 1H), 7.76 (d, J = 3.01 Hz, 1H), 7.35-7.48 (m, 2H), 7.11 (td J = 8.41, 2.76 Hz, 1H), 6.17 (s, IH), 4.09-4.19 (m, IH), 4.05 (dd , J = 12.80,2.76 Hz, (M, 3H), 2.31-2.54 (m, 3H), 2.15-2.28 (m, 1H), 3.91 (d , J = 10.63, 7.23, 7.23, ), 2.08 (t , J = 10.92 Hz, 1H), 1.61-1.75 (m, 1H). MS: Calcd. 548 (MH + ), Measurement 548 (MH + ).
실시예 8Example 8
에틸 (4R)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl] methyl] -4 (4H) -6- [[(8aR) -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [ - (2-bromo-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-브로모-4-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 (8aR)-2,3,4,7,8,8a-헥사하이드로-1H-피롤로[1,2-a]피라진-6-온(이의 합성을 위해 탕 등의 PCT 국제 출원 WO 2012/019426을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 8(8 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.01 Hz, 1H), 7.76(d, J = 3.26 Hz, 1H), 7.36-7.53(m, 2H), 7.12(td, J = 8.34, 2.64 Hz, 1H), 6.18(s, 1H), 4.11-4.17(m, 1H), 4.05(q, J = 6.86 Hz, 2H), 3.97(d, J = 16.81 Hz, 1H), 3.83-3.93(m, 1H), 2.94-3.19(m, 3H), 2.30-2.53(m, 3H), 2.22(ddd, J = 16.75, 12.86, 3.51 Hz, 1H), 2.07(t, J = 10.67 Hz, 1H), 1.61-1.75(m, 1H), 1.15(t, J = 7.15 Hz, 3H). MS: 계산치 562(MH+), 측정치 562(MH+).Instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and hexahydro-pyrazino [1,2-c] [1,3] oxazin- (8aR) -2,3,4,7,8,8a-hexahydro-lH-pyrrolo [1,2-a] pyrazin-6-one The title compound was prepared in analogy to example 1 using the method described in PCT International Application WO 2012/019426 to Tang et al. Example 8 (8 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.01 Hz, 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.36-7.53 (m, 2H), 7.12 (td , J = 8.34, 2.64 Hz, 1H), 6.18 (s, 1H), 4.11-4.17 (m, 1H), 4.05 (q, J = 6.86 Hz, 2H), 3.97 (d, J = 16.81 Hz, 1H) J = 16.75, 12.86, 3.51 Hz, 1 H), 2.07 (t , J = 10.67 Hz, 1H), 1.61-1.75 (m, 1H), 1.15 (t , J = 7.15 Hz, 3H). MS: Calcd. 562 (MH + ), Measurement 562 (MH + ).
실시예 9Example 9
에틸 (4S)-6-[[(8aR)-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-2-일]메틸]-4-(3,4-다이플루오로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl] methyl] -4 < RTI ID = 0.0 > - (3,4- difluorophenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 3,4-다이플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 (8aR)-2,3,4,7,8,8a-헥사하이드로-1H-피롤로[1,2-a]피라진-6-온(이의 합성을 위해, 탕 등의 PCT 국제 출원 WO 2012/019426을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 9(11 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.94-8.05(m, 1H), 7.81(d, J = 3.01 Hz, 1H), 7.14-7.33(m, 3H), 5.74(s, 1H), 4.07-4.23(m, 3H), 4.03(dd, J = 13.05, 2.51 Hz, 1H), 3.83-3.94(m, 2H), 3.09(t, J = 12.55 Hz, 1H), 2.98(d, J = 10.54 Hz, 2H), 2.28-2.52(m, 3H), 2.20(ddt, J = 17.00, 9.29, 3.80, 3.80 Hz, 1H), 2.05(t, J = 10.92 Hz, 1H), 1.59-1.73(m, 1H), 1.24(t, J = 7.15 Hz, 3H). MS: 계산치 502(MH+), 측정치 502(MH+).(Compound D) instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and hexahydro-pyrazino [1,2-c] [1,3] oxazin- (8aR) -2,3,4,7,8,8a-hexahydro-lH-pyrrolo [1,2-a] pyrazin-6-one (for its synthesis, , ≪ / RTI > PCT international application WO < RTI ID = 0.0 > 2012/019426). ≪ / RTI > Example 9 (11 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.94-8.05 (m , 1H), 7.81 (d, J = 3.01 Hz, 1H), 7.14-7.33 (m, 3H), 5.74 (s, 1H) , 4.07-4.23 (m, 3H), 4.03 (dd, J = 13.05, 2.51 Hz, 1H), 3.83-3.94 (m, 2H), 3.09 (t, J = 12.55 Hz, 1H), 2.98 (d, J = 10.54 Hz, 2H), 2.28-2.52 (m, 3H), 2.20 (ddt, J = 17.00,9.29,3.80, 3.80 Hz, 1H), 2.05 (t , J = 10.92 Hz, 1H), 1.59-1.73 m, 1 H), 1.24 (t , J = 7.15 Hz, 3 H). MS: Calcd 502 (MH + ), found 502 (MH + ).
실시예 10Example 10
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[(6-옥소-3,4,7,8,9,9a-헥사하이드로-1H-피리도[1,2-a]피라진-2-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Chloro-3-fluoro-phenyl) -6 - [(6-oxo-3,4,7,8,9,9a-hexahydro-lH-pyrido [ 2-al pyrazin-2-yl) methyl] -2-thiazol-2-yl-l, 4- dihydropyrimidine-
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 1,2,3,4,7,8,9,9a-옥타하이드로피리도[1,2-a]피라진-6-온 하이드로클로라이드 염(제이 앤드 더블유 팜 랩(J & W Pharm Lab), CAS 번호: 151665-85-9; 이의 합성을 위해 겔라르디니(Ghelardini C.) 등의 PCT 국제 출원 WO 2009/103176을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 10(6 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.02(d, J = 3.26 Hz, 1H), 7.96(d, J = 3.26 Hz, 1H), 7.23-7.38(m, 2H), 7.10-7.21(m, 1H), 6.23(s, 1H), 4.56-4.78(m, 2H), 3.82-4.21(m, 5H), 3.05-3.28(m, 4H), 2.40(m, 2H), 1.5-2.21(m, 4 H), 1.21(m, 3H). MS: 계산치 532(MH+), 측정치 532(MH+).Instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and hexahydro-pyrazino [l, 2-c] [1,3] oxazin- Fluoro benzaldehyde, ethylacetoacetate and 1,2,3,4,7,8,9,9a-octahydropyrido [l, 2-a] pyrazin-6-one hydrochloride salt (prepared according to J. & (J & W Pharm Lab), CAS number: 151665-85-9; see Ghelardini C. et al., PCT International Application WO 2009/103176 for its synthesis) The title compound was prepared. Example 10 (6 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.02 (d , J = 3.26 Hz, 1H), 7.96 (d, J = 3.26 Hz, 1H), 7.23-7.38 (m, 2H), 7.10-7.21 (m, 2H), 1.52-21 (m, 2H), 2.63 (s, 3H) (m, 4 H), 1.21 (m, 3 H). MS: Calcd. 532 (MH + ), Measurement 532 (MH + ).
실시예 11Example 11
메틸 (4R)-6-[[(8aR)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -6 - [[(8aR) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-chloro-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 (8aS)-2,5,6,7,8,8a-헥사하이드로-1H-이미다조[1,5-a]피라진-3-온(화합물 H)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 11(11 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.93-8.01(m, 1H), 7.72-7.81(m, 1H), 7.38-7.49(m, 1H), 7.24(dd, J = 8.66, 2.64 Hz, 1H), 7.06(td, J = 8.47, 2.64 Hz, 1H), 6.18(s, 1H), 4.04-4.17(m, 1H), 3.95-4.02(m, 1H), 3.89-3.95(m, 1H), 3.84(dd, J = 13.43, 2.38 Hz, 1H), 3.61(s, 3H), 3.53(t, J = 8.91 Hz, 1H), 3.11-3.21(m, 1H), 3.06(dd, J = 9.41, 4.64 Hz, 1H), 2.92(dd, J = 9.79, 1.51 Hz, 1H), 2.84(dd, J = 11.17, 2.64 Hz, 1H), 2.38(td, J = 11.67, 3.51 Hz, 1H), 2.19-2.29(m, 1H). MS: 계산치 505(MH+), 측정치 505(MH+).(8aS) -2,5,6,7,8,8a-hexahydro-lH-pyrrolo [2,3-c] [1,3] oxazin- Imidazo [l, 5-a] pyrazin-3-one (compound H), the title compound was prepared in analogy to example 1. Example 11 (11 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.93-8.01 (m , 1H), 7.72-7.81 (m, 1H), 7.38-7.49 (m, 1H), 7.24 (dd, J = 8.66, 2.64 1H), 7.06 (td , J = 8.47,2.64 Hz, 1H), 6.18 (s, 1H), 4.04-4. 17 (m, 1H), 3.95-4.02 1H), 3.84 (dd, J = 13.43, 2.38 Hz, 1H), 3.61 (s, 3H), 3.53 (t, J = 8.91 Hz, 1H), 3.11-3.21 (m, 1H), 3.06 (dd, J = 9.41, 4.64 Hz, 1H) , 2.92 (dd, J = 9.79, 1.51 Hz, 1H), 2.84 (dd, J = 11.17, 2.64 Hz, 1H), 2.38 (td, J = 11.67, 3.51 Hz, 1H) , 2.19-2.29 (m, 1 H). MS: calculated for 505 (MH + ), found 505 (MH + ).
(8aS)-2,5,6,7,8,8a-헥사하이드로-1H-이미다조[1,5-a]피라진-3-온(화합물 H)의 제조(8aS) -2,5,6,7,8,8a-hexahydro-1H-imidazo [1,5-a] pyrazin-3-one
단계 1: 물(600 mL) 중 Na2CO3(118 g, 1.11 mol)의 용액에 25℃에서 (2S)-피페라진-2-카복실산 다이하이드로클로라이드 염(30 g, 0.15 mol)을 첨가한 후, 다이-t-부틸 다이카보네이트(112 g, 0.56 mol) 및 테트라하이드로푸란(300 mL)을 첨가하였다. 이어서, 혼합물을 실온에서 추가 20 시간 동안 교반하였다. 반응 혼합물을 진공에서 농축하고, 생성된 용액을 메틸 t-부틸 에터(200 mL)로 3회 추출하여 무극성 종을 제거하였다. 수층을 0℃ 미만으로 냉각한 후 pH 2 내지 3까지 3.0 M HCl로 처리하였다. 이어서, 이를 에틸 아세테이트(500 mL)로 3회 추출하였다. 합한 유기 층을 Na2SO4로 건조한 후 여과하고 진공하에 농축하여 화합물 I(39 g)를 수득하였다. Step 1: water (600 mL) of Na 2 CO 3 (118 g, 1.11 mol) (2 S) in a solution of 25 ℃ -piperazine-2-carboxylic acid dihydrochloride salt (30 g, 0.15 mol) was added Was added followed by di- t- butyl dicarbonate (112 g, 0.56 mol) and tetrahydrofuran (300 mL). The mixture was then stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and the resulting solution was extracted three times with methyl t- butyl ether (200 mL) to remove apolar species. The water layer was cooled to below 0 < 0 > C and then treated with 3.0 M HCl until pH 2-3. It was then extracted three times with ethyl acetate (500 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo to give 39 g of compound I.
단계 2: 테트라하이드로푸란(200 mL) 중 화합물 I(39 g, 0.12 mol)의 용액에 0℃에서 N2 대기하에 BH3ㆍTHF 복합체(240 mL, 0.24 mol)를 적가하였다. 이어서, 혼합물을 실온으로 가온하고 2 내지 3 시간 동안 환류 가열하였다. 혼합물을 0℃에서 MeOH(100 mL)로 급랭하고, 수득된 용액을 진공에서 농축하였다. 잔사를 MeOH(200 mL)에 재용해하고, 상기 용액을 3 내지 4 시간 동안 환류하였다. 이어서, 용매를 제거하여 조질 생성물(45 g)을 수득하였다. 상기 조질 생성물을 실리카 컬럼 크로마토그래피(석유 에터/EtOAc = 10:1 내지 1:1)로 정제하여 화합물 J(31 g)를 수득하였다. Step 2 : To a solution of compound < RTI ID = 0.0 > I (39 g, 0.12 mol) was added dropwise a BH 3 .THF complex (240 mL, 0.24 mol) under N 2 atmosphere at 0 ° C. The mixture was then warmed to room temperature and heated to reflux for 2 to 3 hours. The mixture was quenched with MeOH (100 mL) at 0 C and the resulting solution was concentrated in vacuo. The residue was redissolved in MeOH (200 mL) and the solution was refluxed for 3 to 4 hours. The solvent was then removed to give the crude product (45 g). The crude product was purified by silica column chromatography (petroleum ether / EtOAc = 10: 1 to 1: 1) to give compound J (31 g).
단계 3: 무수 테트라하이드로푸란(230 mL) 중 화합물 J(15 g, 47.41 mmol), Ph3P(16.17 g, 61.63 mmol) 및 프탈이미드(9.07 g, 61.63 mmol)의 용액에 10℃에서 N2 대기하에 테트라하이드로푸란(20 mL) 중 다이이소프로필 아조다이카복실레이트(12.46 g, 61.63 mmol)의 용액을 첨가하였다. 이어서, 혼합물을 추가 2 시간 동안 10℃에서 교반하였다. 혼합물을 1 N HCl(100 mL)로 급랭한 후 EtOAc(300 mL)로 추출하였다. 유기 층을 Na2SO4로 건조하고, 여과한 후 진공에서 농축하여 조질 생성물(50 g)을 수득하였다. 상기 조질 생성물을 석유 에터/EtOAc(200 mL, V/V = 5:1)로 마쇄하여 트라이페닐포스핀 옥사이드 및 다른 불순물이 제거된 조질 생성물(25 g)을 수득하였다. 상기 조질 생성물을 실리카 컬럼 크로마토그래피(석유 에터/EtOAc=20:1)로 정제하여 백색 고체로서 순수한 화합물 K(12 g) 및 약간 불순물이 섞인 화합물 K(4 g)를 수득하였다. Step 3 : To a solution of the compound < RTI ID = 0.0 > Of J (15 g, 47.41 mmol) , Ph 3 P (16.17 g, 61.63 mmol) and phthalimide under N 2 atmosphere at 10 ℃ To a solution of (9.07 g, 61.63 mmol) in tetrahydrofuran (20 mL)-diisopropyl A solution of propyl azodicarboxylate (12.46 g, 61.63 mmol) was added. The mixture was then stirred at < RTI ID = 0.0 > 10 C < / RTI > The mixture was quenched with 1 N HCl (100 mL) and extracted with EtOAc (300 mL). The organic layer was dried with Na 2 SO 4, filtered and then concentrated in vacuo to give the crude product (50 g). The crude product was triturated with petroleum ether / EtOAc (200 mL, V / V = 5: 1) to give crude product (25 g) with triphenylphosphine oxide and other impurities removed. The crude product was purified by silica column chromatography (petroleum ether / EtOAc = 20: 1) to give pure compound K (12 g) and slightly impure compound K (4 g) as a white solid.
단계 4: 에탄올(85 mL) 중 화합물 K(12 g, 26.9 mmol)의 교반된 용액에 실온에서 메틸아민 알코올 용액(85 mL)을 첨가하였다. 이어서, 혼합물을 추가 3 시간 동안 환류 가열하였다. 혼합물을 실온으로 냉각한 후 농축하였다. 생성된 잔사를 물(50 mL)에 용해하고, 이어서 1 N HCl 용액으로 pH 3까지 산성화한 후, 메틸-t-부틸 에터(50 mL)로 3회 추출하였다. 상기 pH를 고체 NaOH로 10으로 조정하고, 혼합물을 에틸 아세테이트(150 mL)로 3회 추출하였다. 유기 층을 건조하고 여과하고, 용매를 감압하에 제거하여 화합물 L(6 g 조질)을 수득하였다. Step 4 : To a stirred solution of compound K (12 g, 26.9 mmol) in ethanol (85 mL) was added methylamine alcohol solution (85 mL) at room temperature. The mixture was then heated to reflux for an additional 3 hours. The mixture was cooled to room temperature and then concentrated. The resulting residue was dissolved in water (50 mL), then acidified to pH 3 with 1 N HCl solution and extracted three times with methyl- t- butyl ether (50 mL). The pH was adjusted to 10 with solid NaOH and the mixture was extracted three times with ethyl acetate (150 mL). The organic layer was dried and filtered, and the solvent was removed under reduced pressure to give compound L (6 g crude).
단계 5: 테트라하이드로푸란(50 mL) 중 나트륨 하이드라이드(1.0 g, 25 mmol)의 교반된 현탁액에 0℃에서 화합물 L(6 g, 19 mmol, 조질)을 첨가하였다. 이어서, 혼합물을 2 시간 동안 환류 가열하였다. 이어서, 추가 NaH(1.0 g, 25 mmol)를 실온에서 상기 혼합물에 첨가하였다. 반응 혼합물을 1 시간 동안 환류한 후, 반응 생성물을 빙수(100 mL)로 급랭하고, 이어서 EtOAc(300 mL)로 추출하였다. 유기 층을 진공에서 증발시켜 조질 생성물(5 g)을 수득하였다. 상기 조질 생성물을 실리카 겔 컬럼 크로마토그래피(EtOAc/MeOH = 200:1)로 정제하여 화합물 M(2.2 g, 40%)을 수득하였다. Step 5: To a stirred suspension of sodium hydride (1.0 g, 25 mmol) in tetrahydrofuran (50 mL) at 0 C was added compound L (6 g, 19 mmol, crude). The mixture was then heated to reflux for 2 hours. Additional NaH (1.0 g, 25 mmol) was then added to the mixture at room temperature. The reaction mixture was refluxed for 1 hour, then the reaction product was quenched with ice water (100 mL) and then extracted with EtOAc (300 mL). The organic layer was evaporated in vacuo to give the crude product (5 g). The crude product was purified by silica gel column chromatography (EtOAc / MeOH = 200: 1) to give compound M (2.2 g, 40%).
단계 6: 다이클로로메탄(30 mL) 중 화합물 M(2.2 g, 9.1 mmol)의 교반된 용액에 TFA(10 mL)를 적가하였다. 반응 혼합물을 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물로서 (8aS)-2,5,6,7,8,8a-헥사하이드로-1H-이미다조[1,5-a]피라진-3-온 트라이플루오로 아세트산 염(화합물 H)을 수득하고, 이를 추가 정제 없이 직접 사용하였다. Step 6: TFA (10 mL) was added dropwise to a stirred solution of compound M (2.2 g, 9.1 mmol) in dichloromethane (30 mL). The reaction mixture was stirred for 1 hour and then the solvent was removed in vacuo to give (8aS) -2,5,6,7,8,8a-hexahydro-1H-imidazo [l, 5-a] pyrazine -3-one trifluoroacetic acid salt (Compound H), which was used directly without further purification.
실시예 12Example 12
메틸 (4R)-6-[[(8aS)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -6 - [[(8aS) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-chloro-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
(2S)-피페라진-2-카복실산 대신에 (2R)-피페라진-2-카복실산을 사용하여 실시예 11과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 12(13 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.91-8.01(m, 1H), 7.71-7.81(m, 1H), 7.42(dd, J = 8.66, 6.15 Hz, 1H), 7.24(dd, J = 8.66, 2.64 Hz, 1H), 7.05(td, J = 8.41, 2.51 Hz, 1H), 6.18(s, 1H), 4.12(d, J = 17.32 Hz, 1H), 3.95-4.05(m, 1H), 3.91(d, J = 17.32 Hz, 1H), 3.77(dd, J = 13.18, 1.88 Hz, 1H), 3.61(s, 3H), 3.56-3.60(m, 1H), 3.08-3.21(m, 2H), 3.01(dd, J = 10.79, 2.76 Hz, 1H), 2.74(d, J = 11.29 Hz, 1H), 2.39(t, J = 10.92 Hz, 1H), 2.24(td, J = 11.67, 3.26 Hz, 1H). MS: 계산치 505(MH+), 측정치 505(MH+).(2 S) - piperazine-2-carboxylic acid instead of (2 R) to -piperazine-2-carboxylic acid The title compound was prepared in analogy to example 11 using was prepared. Example 12 (13 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.91-8.01 (m , 1H), 7.71-7.81 (m, 1H), 7.42 (dd, J = 8.66, 6.15 Hz, 1H), 7.24 (dd, J = 8.66, 2.64 Hz, 1H), 7.05 (td , J = 8.41, 2.51 Hz, 1H), 6.18 (s, 1H), 4.12 (d , J = 17.32 Hz, 1H), 3.95-4.05 ), 3.91 (d , J = 17.32 Hz, 1H), 3.77 (dd , J = 13.18,1.88 Hz, 1H), 3.61 (s, 3H), 3.56-3.60 2H), 3.01 (dd, J = 10.79, 2.76 Hz, 1H), 2.74 (d, J = 11.29 Hz, 1H), 2.39 (t, J = 10.92 Hz, 1H), 2.24 (td, J = 11.67, 3.26 Hz, 1H). MS: calculated for 505 (MH + ), found 505 (MH + ).
실시예 13Example 13
에틸 (4R)-6-[[(8aS)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Ethyl] (4R) -6 - [[(8aS) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-bromo-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
2-클로로-4-플루오로벤즈알데하이드 및 메틸 아세토아세테이트 대신에 2-브로모-4-플루오로벤즈알데하이드 및 에틸 아세토아세테이트를 사용하여 실시예 11과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 13(34 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.91-8.02(m, 1H), 7.78(d, J = 3.01 Hz, 1H), 7.34-7.53(m, 2H), 7.12(td, J = 8.41, 2.76 Hz, 1H), 6.18(s, 1H), 4.15-4.31(m, 1H), 3.93-4.13(m, 4H), 3.76-3.89(m, 1H), 3.61(t, J = 8.91 Hz, 1H), 3.07-3.25(m, 3H), 2.83-3.03(m, 1H), 2.55(br. s., 1H), 2.40(br. s., 1H), 1.14(t, J = 7.15 Hz, 3H). MS: 계산치 563(MH+), 측정치 563(MH+).The title compound was prepared in analogy to example 11 using 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 13 (34 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.91-8.02 (m , 1H), 7.78 (d, J = 3.01 Hz, 1H), 7.34-7.53 (m, 2H), 7.12 (td, J = (M, 1H), 3.61 (t , J = 8.91 Hz, 1H) 1H), 2.40 (br s, 1H), 1.14 (t , J = 7.15 Hz, 1H), 3.07-3.25 (m, 3H), 2.83-3.03 , 3H). MS: Calcd. 563 (MH + ), measurement 563 (MH + ).
실시예 14Example 14
에틸 (4R)-6-[[(8aR)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-브로모-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(4R) -6 - [[(8aR) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazin- - (2-bromo-4-fluoro-phenyl) -2- thiazol-2-yl-l, 4- dihydropyrimidine-
2-클로로-4-플루오로벤즈알데하이드 및 메틸 아세토아세테이트 대신에 2-브로모-4-플루오로벤즈알데하이드 및 에틸 아세토아세테이트를 사용하여 실시예 12와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 14(34 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.92-8.01(m, 1H), 7.78(d, J = 3.26 Hz, 1H), 7.35-7.56(m, 2H), 7.12(td, J = 8.41, 2.76 Hz, 1H), 6.18(s, 1H), 4.17-4.32(m, 1H), 3.96-4.16(m, 4H), 3.89(dd, J = 13.55, 2.51 Hz, 1H), 3.49-3.64(m, 1H), 3.17-3.28(m, 1H), 2.97-3.17(m, 3H), 2.31-2.68(m, 2H), 1.14(t, J = 7.15 Hz, 3H). MS: 계산치 563(MH+), 측정치 563(MH+).The title compound was prepared in analogy to example 12 using 2-bromo-4-fluorobenzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 14 (34 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.92-8.01 (m , 1H), 7.78 (d, J = 3.26 Hz, 1H), 7.35-7.56 (m, 2H), 7.12 (td, J = (M, 4H), 3.89 (dd , J = 13.55, 2.51 Hz, 1H), 3.49-3.64 (m, 1H), 3.17-3.28 (m, 1H), 2.97-3.17 (m, 3H), 2.31-2.68 (m, 2H), 1.14 (t , J = 7.15 Hz, 3H). MS: Calcd. 563 (MH + ), measurement 563 (MH + ).
실시예 15Example 15
메틸 (4R)-6-[[(8aR)-1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl) methyl] -4- (4-methylpiperazin-1-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 N)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 황색 고체로서 실시예 15(11 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.89-7.97(m, 1H), 7.71-7.81(m, 1H), 7.38-7.53(m, 1H), 7.24(dd, J = 8.78, 2.76 Hz, 1H), 7.07(td, J = 8.41, 2.76 Hz, 1H), 6.19(s, 1H), 4.28-4.40(m, 1H), 4.15-4.26(m, 1H), 3.92-4.07(m, 2H), 3.61(s, 3H), 3.36(d, J = 4.77 Hz, 1H), 3.20-3.29(m, 1H), 2.78-2.86(m, 1H), 2.42(t, J = 11.17 Hz, 1H), 2.29(td, J = 11.86, 3.64 Hz, 1H). MS: 계산치 519(MH+), 측정치 519(MH+).Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(1,3- dioxo-5,6,8,8a-tetrahydroimidazo [ 7-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound N) was SFC chiral separated to give the title compound. Example 15 (11 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.89-7.97 (m , 1H), 7.71-7.81 (m, 1H), 7.38-7.53 (m, 1H), 7.24 (dd, J = 8.78, 2.76 1H), 7.07 (td , J = 8.41, 2.76 Hz, IH), 6.19 (s, IH), 4.28-4.40 (m, IH), 4.15-4.26 2H), 3.61 (s, 3H ), 3.36 (d, J = 4.77 Hz, 1H), 3.20-3.29 (m, 1H), 2.78-2.86 (m, 1H), 2.42 (t, J = 11.17 Hz, 1H ), 2.29 (td , J = 11.86,3.64 Hz, 1 H). MS: Calcd. 519 (MH + ), Measurement 519 (MH + ).
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 N)의 제조Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(1,3- dioxo-5,6,8,8a-tetrahydroimidazo [ Yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound N)
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 6,7,8,8a-테트라하이드로-5H-이미다조[1,5-a]피라진-1,3-다이온(이의 합성을 위해 WO 2010/23480을 참조한다)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다.Tetrahydro-5H-imidazo [l, 5-a] pyrimidine instead of hexahydro-pyrazino [l, ] Pyrazine-1,3-dione (see WO 2010/23480 for its synthesis), the title compound was prepared in analogy to example 1.
실시예 16Example 16
메틸 (4R)-6-[[(8aS)-1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Yl) methyl] -4- (4-methylpiperazin-1-yl) (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-
실시예 15의 메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,3-다이옥소-5,6,8,8a-테트라하이드로이미다조[1,5-a]피라진-7-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 N)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 황색 고체로서 실시예 16(10 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.90-7.97(m, 1H), 7.76(d, J = 3.26 Hz, 1H), 7.37-7.49(m, 1H), 7.24(dd, J = 8.78, 2.76 Hz, 1H), 7.06(td, J = 8.41, 2.76 Hz, 1H), 6.19(s, 1H), 4.24-4.36(m, 1H), 4.13-4.22(m, 1H), 4.09(dd, J = 13.43, 2.89 Hz, 1H), 3.98-4.06(m, 1H), 3.61(s, 3H), 3.27(td, J = 12.67, 3.76 Hz, 1H), 3.18(dd, J = 11.04, 4.27 Hz, 1H), 2.97-3.04(m, 1H), 2.44(td, J = 11.80, 3.76 Hz, 1H), 2.29(t, J = 11.17 Hz, 1H). MS: 계산치 519(MH+), 측정치 519(MH+).Example 15 (2-Chloro-4-fluorophenyl) methyl (4 R) -6-4 - [(1,3- dioxo -5,6,8,8a- tetrahydro-imidazo [1 , 5-a] pyrazin-7-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound N) . Example 16 (10 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.90-7.97 (m , 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.37-7.49 (m, 1H), 7.24 (dd, J = 1H , J = 8.41, 2.76 Hz, 1H), 7.06 (td , J = 8.41, 2.76 Hz, 1H), 6.19 , J = 13.43, 2.89 Hz, 1H), 3.98-4.06 (m, 1H), 3.61 (s, 3H), 3.27 (td, J = 12.67, 3.76 Hz, 1H), 3.18 (dd, J = 11.04, 4.27 1H), 2.97-3.04 (m, 1H), 2.44 (td , J = 11.80, 3.76 Hz, 1H), 2.29 (t , J = 11.17 Hz, 1H). MS: Calcd. 519 (MH + ), Measurement 519 (MH + ).
실시예 17Example 17
메틸 (4R)-6-[[(3aS)-1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -6 - [[(3aS) -1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [1,2,5] thiadiazolo [ (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl- l, 4- dihydropyrimidine-5-carboxylate
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 O)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 황색 고체로서 실시예 17(14 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.93-8.00(m, 1H), 7.77(d, J = 3.01 Hz, 1H), 7.44(dd, J = 8.78, 6.02 Hz, 1H), 7.25(dd, J = 8.66, 2.64 Hz, 1H), 7.06(td, J = 8.41, 2.76 Hz, 1H), 6.18(s, 1H), 4.12-4.26(m, 1H), 3.97-4.10(m, 1H), 3.58-3.70(m, 4H), 3.42-3.55(m, 2H), 3.03-3.20(m, 4H), 2.63-2.76(m, 1H), 2.42(t, J = 10.54 Hz, 1H). MS: 계산치 541(MH+), 측정치 541(MH+).Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [ Thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound O) was reacted with SFC Chiral separation afforded the title compound. Example 17 (14 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.93-8.00 (m , 1H), 7.77 (d, J = 3.01 Hz, 1H), 7.44 (dd, J = 8.78, 6.02 Hz, 1H), 7.25 (dd , J = 8.66, 2.64 Hz, 1H), 7.06 (td , J = 8.41, 2.76 Hz, 1H), 6.18 (s, 1H), 4.12-4.26 ), 3.58-3.70 (m, 4H), 3.42-3.55 (m, 2H), 3.03-3.20 (m, 4H), 2.63-2.76 (m, 1H), 2.42 (t , J = 10.54 Hz, 1H). MS: Calcd. 541 (MH + ), measurement 541 (MH + ).
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 O)의 제조Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6 - [(1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [ , 5] thiadiazolo [2,3- a] pyrazin-5-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 헥사하이드로-1-티아-2,5,7a-트라이아자-인덴 1,1-다이옥사이드(화합물 P)를 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다.(Compound D) instead of hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one (Compound P), the title compound was prepared in analogy to example 1. < RTI ID = 0.0 >
헥사하이드로-1-티아-2,5,7a-트라이아자-인덴 1,1-다이옥사이드(화합물 P)의 제조Hexahydro-1-thia-2,5,7a-triaza-indene 1,1-dioxide (Compound P)
피리딘(2 mL) 중 3-아미노메틸-피페라진-1-카복실산 t-부틸 에스터(CAS 번호: 1376099-80-7, 베팜)(215 mg, 1.0 mmol)의 교반된 용액에 설파미드(1.5 mmol)를 첨가하였다. 반응 혼합물을 150℃로 6 시간 동안 마이크로파하에 가열하였다. 용매를 진공에서 제거하고, 잔사를 다이클로로메탄(3 mL) 및 TFA(1 mL)에 용해하였다. 반응 혼합물을 1 시간 동안 교반하고, 용매를 진공에서 제거하여 조질 화합물 P를 수득하고, 이를 추가 정제 없이 직접 사용하였다. LC/MS: 계산치 178(MH+), 측정치 178(MH+).To a stirred solution of 3-aminomethyl-piperazine-1-carboxylic acid tert - butyl ester (CAS # 1376099-80-7, Befam) (215 mg, 1.0 mmol) in pyridine (2 mL) ). The reaction mixture was heated to 150 < 0 > C for 6 hours under microwave. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (3 mL) and TFA (1 mL). The reaction mixture was stirred for 1 hour and the solvent was removed in vacuo to give crude Compound P which was used directly without further purification. LC / MS: calculated 178 (MH + ), found 178 (MH + ).
실시예 18Example 18
메틸 (4R)-6-[[(3aR)-1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -6 - [[(3aR) -1,1-dioxo-2,3,3a, 4,6,7- hexahydro- [1,2,5] thiadiazolo [ (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl- l, 4- dihydropyrimidine-5-carboxylate
실시예 17의 메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[(1,1-다이옥소-2,3,3a,4,6,7-헥사하이드로-[1,2,5]티아다이아졸로[2,3-a]피라진-5-일)메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 O)를 SFC 키랄 분리하여 표제 화합물을 제조하였다. 황색 고체로서 실시예 18(28 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.26 Hz, 1H), 7.79(d, J = 3.26 Hz, 1H), 7.45(dd, J = 8.78, 6.02 Hz, 1H), 7.25(dd, J = 8.78, 2.51 Hz, 1H), 7.07(td, J = 8.41, 2.76 Hz, 1H), 6.19(s, 1H), 4.32(d, J = 16.81 Hz, 1H), 4.09(d, J = 16.81 Hz, 1H), 3.67-3.81(m, 1H), 3.58-3.66(m, 3H), 3.46-3.58(m, 2H), 3.29-3.31(m, 1H), 3.23(dd, J = 9.79, 8.78 Hz, 1H), 3.02-3.19(m, 2H), 2.69(q, J = 10.79 Hz, 2H). MS: 계산치 541(MH+), 측정치 541(MH+).(4R) -4- (2-Chloro-4-fluoro-phenyl) -6 - [(1,1-dioxo-2,3,3a, 4,6,7- hexahydro- Thiadiazolo [2,3-a] pyrazin-5-yl) methyl] -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate O) < / RTI > was SFC enantiomeric to give the title compound. Example 18 (28 mg) was obtained as a yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.26 Hz, 1H), 7.79 (d, J = 3.26 Hz, 1H), 7.45 (dd, J = 8.78, 6.02 Hz, 1H ), 7.25 (dd, J = 8.78, 2.51 Hz, 1H), 7.07 (td, J = 8.41, 2.76 Hz, 1H), 6.19 (s, 1H), 4.32 (d, J = 16.81 Hz, 1H), 4.09 (d , J = 16.81 Hz, 1H), 3.67-3.81 (m, 1H), 3.58-3.66 (m, 3H), 3.46-3.58 (m, 2H), 3.29-3.31 J = 9.79, 8.78 Hz, 1H), 3.02-3.19 (m, 2H), 2.69 (q , J = 10.79 Hz, 2H). MS: Calcd. 541 (MH + ), measurement 541 (MH + ).
실시예 19Example 19
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 19(12 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.92-8.02(m, 1H), 7.70-7.80(m, 1H), 7.21-7.36(m, 2H), 7.10-7.21(m, 1H), 6.19-6.28(m, 1H), 3.99-4.14(m, 3H), 3.81-3.96(m, 3H), 3.47-3.56(m, 1H), 3.38-3.44(m, 1H), 3.27-3.32(m, 1H), 3.15-3.25(m, 1H), 3.07-3.14(m, 1H), 2.79-2.96(m, 2H), 2.30-2.41(m, 1H), 2.13-2.23(m, 1H), 1.20(d, J = 2.76 Hz, 6H), 1.13(m, 3H). MS: 계산치 619(MH+), 측정치 619(MH+).Instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and hexahydro-pyrazino [l, 2-c] [1,3] oxazin- Fluoro benzaldehyde, ethyl acetoacetate and 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- The title compound was prepared in analogy to example 1 using 2,2-dimethyl-propanoic acid (compound Q). Example 19 (12 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.92-8.02 (m , 1H), 7.70-7.80 (m, 1H), 7.21-7.36 (m, 2H), 7.10-7.21 (m, 1H), (M, 1H), 3.99-4.14 (m, 3H), 3.81-3.96 (m, 3H), 3.47-3.56 2H), 2.30-2.41 (m, 1H), 2.13-2.23 (m, 1H), 1.20 (m, (d , J = 2.76 Hz, 6H), 1.13 (m, 3H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
3-[(3 - [( 8aS8aS )-3-옥소-1,5,6,7,8,8a-) -3-oxo-1,5,6,7,8,8a- 헥사하이드로이미다조[1,5-a]피라진Hexahydroimidazo [1,5-a] pyrazine -2-일]-2,2-다이메틸-프로판산(화합물 Q)의 제조-2-yl] -2,2-dimethyl-propanoic acid (Compound Q)
단계 1: 포화 NaHCO3(45 mL) 및 EtOAc(45 mL) 중 (R)-4-N-boc-2-하이드록시메틸-피페라진(CAS 번호: 314741-40 내지 7, 베팜; 이의 합성을 위해 문헌[Gao H., Renslo A. R. J. Org. Chem. 2007, 72, 8591-8592]을 참조한다)(6 g, 27.8 mmol)의 교반된 용액에 0℃에서 벤질 클로로포름에이트(7.13 g, 41.7 mmol)를 적가하였다. 이어서, 반응 혼합물을 실온에서 15 시간 동안 교반하였다. 반응 생성물을 EtOAc(60 mL)로 희석하고, 유기 층을 분리하고 수층을 EtOAc(35 mL)로 추출하였다. 합한 유기 층을 Na2SO4로 건조하고, 용액을 농축하여 조질 생성물을 수득하였다. 상기 조질 생성물을 실리카 컬럼 크로마토그래피(석유 에터/EtOAc = 10:1 내지 1:1)로 정제하여 화합물 R(6.7 g)을 수득하였다. Step 1: To a solution of ( R ) -4- N- boc-2-hydroxymethyl-piperazine (CAS No. 314741-40-7, Befam; Synthesis thereof in 45 mL of saturated NaHCO 3 and 45 mL of EtOAc reference to [Gao H., Renslo AR J. Org . Chem. 2007, 72, 8591-8592] and references) (6 g, 27.8 mmol) benzyl chloroformate (7.13 g, 41.7 eseo 0 ℃ to a stirred solution of the mmol) was added dropwise. The reaction mixture was then stirred at room temperature for 15 hours. The reaction product was diluted with EtOAc (60 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were dried with Na 2 SO 4, and the solution is concentrated to give the crude product. The crude product was purified by silica column chromatography (petroleum ether / EtOAc = 10: 1 to 1: 1) to give compound R (6.7 g).
단계 2: -78℃에서 무수 다이클로로메탄(80 mL) 중 옥살릴 클로라이드(3.64 g, 28.65 mmol)의 교반된 용액에 다이메틸 설폭사이드(4.47 g, 57.3 mmol)를 적가하였다. 10 분 후, 다이클로로메탄(20 mL) 중 화합물 R(6.7 g, 19.1 mmol)의 용액을 적가하였다. 혼합물을 -78℃에서 30 분 동안 교반한 후, N,N-다이이소프로필에틸아민(14.78 g, 114.6 mmol)을 첨가하고, 반응 혼합물을 30 분 동안 교반하였다. 반응 혼합물을 0℃로 30 분간에 걸쳐서 천천히 가온한 후, 이를 다이클로로메탄(80 mL)으로 희석하고, 5% 수성 시트르산(10 mL) 및 염수로 세척한 후 Na2SO4로 건조하였다. 여과 후, 혼합물을 진공에서 농축하여 조질 생성물 S(7 g)를 수득하였다. Step 2: Dimethyl sulfoxide (4.47 g, 57.3 mmol) was added dropwise to a stirred solution of oxalyl chloride (3.64 g, 28.65 mmol) in anhydrous dichloromethane (80 mL) at -78 ° C. After 10 minutes, a solution of the compound < RTI ID = 0.0 > R < / RTI > (6.7 g, 19.1 mmol). The mixture was stirred at -78 < 0 > C for 30 minutes, then N, N -diisopropylethylamine (14.78 g, 114.6 mmol) was added and the reaction mixture was stirred for 30 minutes. Then it was slowly warmed over a period of 30 minutes to the reaction mixture at 0 ℃, diluted with dichloromethane (80 mL), washed with 5% aqueous citric acid (10 mL) and brine and dried over Na 2 SO 4. After filtration, the mixture was concentrated in vacuo to give crude product S (7 g).
단계 3: 무수 DCM(100 mL) 중 에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염(3.4 g, 18.6 mmol)의 교반된 용액에 실온에서 DIPEA(2.6 g, 27.3 mmol)를 첨가하였다. 이어서, 화합물 S(7 g, 20 mmol)를 첨가한 후, NaBH(OAc)3(6.3 g, 29.8 mmol) 및 AcOH(1.5 mL)를 첨가하였다. 반응 혼합물을 16 시간 동안 실온에서 교반하였다. 물(100 mL)을 첨가하고, 혼합물을 DCM(100 mL)으로 추출하였다. 유기 층을 건조하고 진공에서 농축 건조하여 조질 화합물 T(7.3 g)를 수득하였다. Step 3: To a stirred solution of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt (3.4 g, 18.6 mmol) in anhydrous DCM (100 mL) at room temperature was added DIPEA (2.6 g, 27.3 mmol) Was added. Compound S (7 g, 20 mmol) was then added followed by NaBH (OAc) 3 (6.3 g, 29.8 mmol) and AcOH (1.5 mL). The reaction mixture was stirred at room temperature for 16 hours. Water (100 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was dried and concentrated to dryness in vacuo to give crude Compound T (7.3 g).
단계 4: EtOH(100 mL) 중 화합물 T(3.3 g, 6.9 mmol)의 용액에 Pd/C(1 g)를 첨가하였다. 이어서, 혼합물을 50℃에서 3 시간 동안 수소 대기하에(50 Psi) 교반하였다. 반응 혼합물을 여과하고 여액을 진공에서 농축하여 화합물 U(1.8 g)를 수득하였다. Step 4: To a solution of < RTI ID = 0.0 > T (3.3 g, 6.9 mmol) in THF (5 mL) was added Pd / C (1 g). The mixture was then stirred under a hydrogen atmosphere (50 Psi) at 50 < 0 > C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give compound U (1.8 g).
단계 5: 무수 다이클로로메탄(60 mL) 중 화합물 U(1.8 g, 5.24 mmol)의 용액에 0℃에서 N,N-다이이소프로필에틸아민(3.4 g, 26.2 mmol)을 첨가하였다. 이어서, 트라이포스겐(783 mg, 2.62 mmol)을 0℃에서 첨가하고, 혼합물을 10 내지 15℃에서 16 시간 동안 교반하였다. 물(50 mL)을 첨가하고, 혼합물을 다이클로로메탄(60 mL)으로 추출한 후, Na2SO4로 건조하였다. 용매를 진공에서 제거하여 조질 생성물을 수득하였다. 상기 조질 생성물을 실리카 컬럼 크로마토그래피(석유 에터/EtOAc = 5:1 내지 1:1)로 정제하여 화합물 V(1.3 g)를 수득하였다. Step 5: To a solution of compound U (1.8 g, 5.24 mmol) in anhydrous dichloromethane (60 mL) at 0 C was added N, N -diisopropylethylamine (3.4 g, 26.2 mmol). Triphosgene (783 mg, 2.62 mmol) was then added at 0 < 0 > C and the mixture was stirred at 10-15 [deg.] C for 16 h. Water (50 mL) was added and the mixture was extracted with dichloromethane (60 mL) and then dried over Na 2 SO 4 . The solvent was removed in vacuo to give the crude product. The crude product was purified by silica column chromatography (petroleum ether / EtOAc = 5: 1 to 1: 1) to give compound V (1.3 g).
단계 6: THF(3 ml) 중 화합물 V(240 mg, 0.64 mmol)의 교반된 용액에 실온에서 H2O(1 mL) 중 LiOHㆍH2O(215 mg, 5.10 mmol)의 용액을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반한 후, 이를 0℃에서 1 N HCl로 pH 3 내지 4로 산성화하였다. 이어서, 혼합물을 농축하고, 톨루엔으로 공비 건조하여 조질 생성물을 수득하고, 이를 다이클로로메탄(2 mL)에 용해하고, 실온에서 트라이플루오로아세트산(2 mL)으로 처리하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 수득하고, 이를 직접 사용하였다. Step 6: To a solution of THF (3 ml) of compound V (240 mg, 0.64 mmol) LiOH and H 2 O (215 mg, 5.10 mmol) in H 2 O (1 mL) at room temperature was added dropwise a solution of . The reaction mixture was stirred overnight at room temperature and then acidified to pH 3-4 with 1 N HCl at 0 < 0 > C. The mixture was then concentrated and azeotropically dried in toluene to give the crude product which was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid (compound Q) was obtained and used directly.
실시예 20Example 20
3-[(8aS)-7-[[(4R)-4-(2-클로로페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메틸-프로판산3 - [(8aS) -7 - [[(4R) -4- (2-Chlorophenyl) -5- ethoxycarbonyl-2-thiazol-2-yl-1,4- dihydropyrimidine- -Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-
2-클로로-4-플루오로벤즈알데하이드 및 에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 2-클로로벤즈알데하이드 및 메틸 3-아미노-2-메틸-프로판오에이트 하이드로클로라이드 염(화합물 W)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 20(20 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.01 Hz, 1H), 7.75(d, J = 3.01 Hz, 1H), 7.42(d, J = 7.78 Hz, 2H), 7.14-7.36(m, 2H), 6.22(s, 1H), 3.97-4.16(m, 3H), 3.79-3.97(m, 3H), 3.43-3.59(m, 2H), 3.26-3.43(m, 2H), 3.05-3.26(m, 2H), 2.80-2.99(m, 2H), 2.65-2.80(m, 1H), 2.35(t, J = 10.79 Hz, 1H), 2.19(q, J = 10.46 Hz, 1H), 1.06-1.24(m, 5H). MS: 계산치 587(MH+), 측정치 587(MH+).Chloro-4-fluorobenzaldehyde and ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt with 2-chlorobenzaldehyde and methyl 3-amino-2-methyl-propanoate hydrochloride The title compound was prepared in analogy to example 19 using the chloride salt (compound W). Example 20 (20 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.01 Hz, 1H), 7.75 (d, J = 3.01 Hz, 1H), 7.42 (d, J = 7.78 Hz, 2H), 3H), 3.43-3.59 (m, 2H), 3.26-3.43 (m, 2H), 3.74-3. (M, 2H), 2.65-2.80 (m, 1H), 2.35 (t , J = 10.79 Hz, 1H), 2.19 (q , J = 10.46 Hz, 1H), 1.06-1.24 (m, 5H). MS: Calculated 587 (MH < + & gt ; ), found 587 (MH < + & gt ; ).
메틸 3-아미노-2-메틸-프로판오에이트 하이드로클로라이드 염(화합물 W)의 제조Preparation of methyl 3-amino-2-methyl-propanoate hydrochloride salt (Compound W)
MeOH(50 mL) 중 DL-3-아미노이소부티르산(CAS 번호: 144-90-1, 알드리치(Aldrich))(2.7 g, 26.4 mmol)의 용액에 0℃에서 N2 대기하에 SOCl2(6.17 g, 52.8 mmol)를 적가하였다. 반응 생성물을 18 시간 동안 환류하였다. 용매를 진공에서 제거하여 조질 화합물 W를 수득하고, 이를 다음 단계에서 직접 사용하였다.MeOH (50 mL) of DL-3- amino-isobutyric acid (CAS number: 144-90-1, Aldrich (Aldrich)) SOCl 2 (6.17 g under a N 2 atmosphere at 0 ℃ To a solution of (2.7 g, 26.4 mmol) , 52.8 mmol) was added dropwise. The reaction product was refluxed for 18 hours. The solvent was removed in vacuo to give crude Compound W, which was used directly in the next step.
실시예 21Example 21
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메틸-프로판산3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- mountain
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 3-아미노-2-메틸-프로판오에이트 하이드로클로라이드 염(화합물 W)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 21(10 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.26 Hz, 1H), 7.76(d, J = 3.26 Hz, 1H), 7.21-7.36(m, 2H), 7.10-7.21(m, 1H), 6.24(s, 1H), 3.98-4.17(m, 3H), 3.79-3.98(m, 3H), 3.42-3.58(m, 2H), 3.24-3.42(m, 2H), 3.08-3.24(m, 2H), 2.79-2.96(m, 2H), 2.73(ddt, J = 10.63, 7.00, 3.73, 3.73 Hz, 1H), 2.30-2.43(m, 1H), 2.13-2.27(m, 1H), 1.08-1.24(m, 5H). MS: 계산치 605(MH+), 측정치 605(MH+).Amino-2-methyl-propanoate hydrochloride salt (Compound W) in place of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt, the title compound . Example 21 (10 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.26 Hz, 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.21-7.36 (m, 2H), 7.10-7.21 (m, 2H), 3.24-3.42 (m, 2H), 3.08 (m, 3H) 1H), 2.30-2.43 (m, 1H), 2.13-2.27 (m, 2H), 2.73 (m, 2H), 2.73 (ddt, J = 10.63, 7.00, 3.73, 3.73 Hz, 1H), 1.08-1.24 (m, 5H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
실시예 22Example 22
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산Methyl-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid
2-클로로-4-플루오로벤즈알데하이드 대신에 2-메틸-3,4-다이플루오로벤즈알데하이드를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 22(2 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.88-8.00(m, 1H), 7.69-7.80(m, 1H), 6.95-7.13(m, 2H), 5.88-5.99(m, 1H), 4.03-4.16(m, 2H), 3.79-3.97(m, 3H), 3.47-3.54(m, 1H), 3.36-3.44(m, 2H), 3.28-3.31(m, 1H), 3.07-3.24(m, 2H), 2.76-2.94(m, 2H), 2.57(d, J = 2.26 Hz, 3H), 2.31-2.42(m, 1H), 2.12-2.22(m, 1H), 1.10-1.24(m, 9H). MS: 계산치 617(MH+), 측정치 617(MH+).The title compound was prepared in analogy to example 19 using 2-methyl-3,4-difluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde. Example 22 (2 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.88-8.00 (m , 1H), 7.69-7.80 (m, 1H), 6.95-7.13 (m, 2H), 5.88-5.99 (m, 1H), 2H), 3.79-3.97 (m, 3H), 3.47-3.54 (m, 1H), 3.36-3.44 2H), 2.76-2.94 (m, 2H), 2.57 (d , J = 2.26 Hz, 3H), 2.31-2.42 ). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
실시예 23Example 23
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-메톡시-1,1-다이메틸-2-옥소-에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(2-chloro-3-fluoro-phenyl) -6- [[2- (2-methoxy- 5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-7-yl] methyl] -2- thiazol- - carboxylate
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 3-아미노-2-메틸-프로판오에이트 하이드로클로라이드 염을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 23(4 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.94-8.03(m, 1H), 7.72-7.82(m, 1H), 7.22-7.38(m, 2H), 7.11-7.20(m, 1H), 6.25(s, 1H), 4.10-4.22(m, 1H), 3.85-4.02(m, 2H), 3.76-3.84(m, 1H), 3.74(d, J = 1.00 Hz, 2H), 3.59-3.71(m, 1H), 3.12-3.30(m, 2H), 2.76-3.03(m, 2H), 2.20-2.52(m, 2H), 1.50(t, J = 7.78 Hz, 6H), 1.14(t, J = 7.03 Hz, 3H). MS: 계산치 619(MH+), 측정치 619(MH+).The title compound was prepared in analogy to example 19 using methyl 3-amino-2-methyl-propanoate hydrochloride salt instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 23 (4 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.94-8.03 (m , 1H), 7.72-7.82 (m, 1H), 7.22-7.38 (m, 2H), 7.11-7.20 (m, 1H), (M, 2H), 3.76-3.84 (m, 1H), 3.74 (d, J = 1.00 Hz, 2H), 3.59-3.71 J = 7.78 Hz, 6H), 1.14 (t , J = 7.8 Hz, 2H), 2.20-3. 7.03 Hz, 3H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
실시예 24Example 24
메틸 7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-2,5,6,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-카복실레이트Methyl 7 - [[(4R) -4- (2-chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- -Yl] methyl] -3-oxo-2,5,6,8-tetrahydro-1H-imidazo [1,5- a] pyrazine-8a-
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 메틸 3-옥소-1,2,5,6,7,8-헥사하이드로이미다조[1,5-a]피라진-8a-카복실레이트(화합물 X)를 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 24(5 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.26 Hz, 1H), 7.76(d, J = 3.26 Hz, 1H), 7.27-7.35(m, 1H), 7.26(s, 1H), 7.16(s, 1H), 6.22(s, 1H), 3.97-4.14(m, 3H), 3.87-3.95(m, 1H), 3.78-3.85(m, 1H), 3.67(s, 3H), 3.46(d, J = 9.79 Hz, 2H), 3.35-3.42(m, 2H), 2.87-2.99(m, 1H), 2.45-2.55(m, 1H), 2.29-2.42(m, 1H), 1.12(t, J = 7.15 Hz, 3H). MS: 계산치 577(MH+), 측정치 577(MH+).Instead of 2-chloro-4-fluorobenzaldehyde, methyl acetoacetate and hexahydro-pyrazino [l, 2-c] [1,3] oxazin- (Compound X) was used instead of ethyl acetoacetate and methyl 3-oxo-1,2,5,6,7,8-hexahydroimidazo [1,5-a] pyrazine-8a- The title compound was prepared in analogy to example 1, Example 24 (5 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.26 Hz, 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.27-7.35 (m, 1H), 7.26 (s 1H), 3.67 (s, 3H), 3.87-3.95 (m, 1H), 3.78-3.85 1H), 3.46 (d , J = 9.79 Hz, 2H), 3.35-3.42 (m, 2H), 2.87-2.99 1.12 (t , J = 7.15 Hz, 3 H). MS: Calculated 577 (MH < + & gt ; ), found 577 (MH < + & gt ; ).
메틸 3-옥소-1,2,5,6,7,8-헥사하이드로이미다조[1,5-a]피라진-8a-카복실레이트(화합물 X)의 제조Preparation of methyl 3-oxo-1,2,5,6,7,8-hexahydroimidazo [1,5-a] pyrazine-8a-carboxylate (Compound X)
단계 1: 피페라진-1,3-다이카복실산 1-t-부틸 에스터 3-메틸 에스터(244 mg, 1.0 mmol)를 다이클로로메탄(5 mL)에 용해한 후 실온에서 추가 TEA(202 mg, 2.0 mmol) 및 벤질 클로로포름에이트(170 mg, 1.0 mmol)를 순차적으로첨가하였다. 반응 생성물을 1 시간 동안 교반한 후, 이를 다이클로로메탄으로 희석한 후, 물 및 염수로 세척하였다. 용매를 농축하여 조질 화합물 Y를 수득하고, 이를 추가 정제 없이 직접 사용하였다. Step 1 : Piperazine-l, 3-dicarboxylic acid l - tert - butyl ester 3-methyl ester (244 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL) followed by additional TEA (202 mg, 2.0 mmol ) And benzyl chloroformate (170 mg, 1.0 mmol) were added successively. The reaction product was stirred for 1 hour, diluted with dichloromethane, and washed with water and brine. The solvent was concentrated to give crude Compound Y, which was used directly without further purification.
단계 2: 이전 단계로부터의 피페라진-1,2,4-트라이카복실산 1-벤질 에스터 4-t-부틸 에스터 2-메틸 에스터(화합물 Y)를 -78℃에서 용해한 후, LDA(2 M, 1 mL, 2 mmol)를 적가하였다. 반응 혼합물을 2 시간 동안 -78℃에서 교반한 후, THF(2 mL) 중 2-브로모메틸-이소인돌-1,3-다이온(239 mg, 1 mmol)을 첨가하였다. 반응 혼합물을 밤새 교반하였다. 용매를 진공에서 제거하고, 잔사를 석유 에터로 마쇄하였다. 고체를 여과로 수집하고, 물로 세척한 후 진공에서 건조하여 화합물 Z를 수득하였다. Step 2 : Piperazine-1,2,4-tricarboxylic acid 1-benzyl ester from the previous step 4 -t- Butyl ester 2-methyl ester (compound Y) was dissolved at -78 ° C and LDA mL, 2 mmol) was added dropwise. The reaction mixture was stirred for 2 h at -78 <0> C and then 2-bromomethyl-isoindole-l, 3-dione (239 mg, 1 mmol) in THF (2 mL) was added. The reaction mixture was stirred overnight. The solvent was removed in vacuo and the residue was triturated with petroleum ether. The solids were collected by filtration, washed with water and dried in vacuo to give compound Z.
단계 3: 단계 2로부터의 2-(1,3-다이옥소-1,3-다이하이드로-이소인돌-2-일메틸)-피페라진-1,2,4-트라이카복실산 1-벤질 에스터 4-t-부틸 에스터 2-메틸 에스터(화합물 Z)를 EtOH(3 mL) 및 N2H4 용액(1 mL)에 용해하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 고체를 여과 제거하고, 여액을 진공에서 농축하였다. 조질 오일을 MeOH(10 mL)에 용해하고, H2 대기하에 밤새 Pd/C(50 mg)로 교반하였다. 여과 후, 용매를 진공에서 농축하여 오일로서 조질 화합물 AA(100 mg)을 수득하고, 이를 다음 단계에서 추가 정제 없이 직접 사용하였다. Step 3 : 2- (l, 3-Dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -piperazine- l, 2,4-tricarboxylic acid l- benzyl ester 4- the t- butyl ester 2-methyl ester (compound Z) was dissolved in EtOH (3 mL) and N 2 H 4 solution (1 mL). The reaction mixture was stirred overnight at room temperature. The solid was filtered off and the filtrate was concentrated in vacuo. The crude oil was dissolved in MeOH (10 mL) and stirred with Pd / C (50 mg) overnight under an H 2 atmosphere. After filtration, the solvent was concentrated in vacuo to give crude compound AA (100 mg) as an oil which was used directly in the next step without further purification.
단계 4: 단계 3으로부터의 3-아미노메틸-피페라진-1,3-다이카복실산 1-t-부틸 에스터 3-메틸 에스터(화합물 AA)를 다이클로로메탄(4 mL) 및 DIPEA(1 mL)에 용해한 후, 트라이포스겐(108 mg, 0.36 mmol)을 실온에서 첨가하였다. 반응 혼합물을 30 분 동안 교반한 후, 용매를 진공에서 제거하였다. 잔사를 다이클로로메탄(3 mL) 및 TFA(1 mL)에 용해하였다. 반응 혼합물을 1 시간 동안 실온에서 교반하고, 용매를 진공에서 제거하여 조질 화합물 X를 수득하고, 이를 추가 정제 없이 직접 사용하였다. Step 4 : To a solution of 3-aminomethyl-piperazine-l, 3-dicarboxylic acid l - tert - butyl ester 3-methyl ester (compound AA) from step 3 in dichloromethane (4 mL) and DIPEA (1 mL) After dissolution, triphosgene (108 mg, 0.36 mmol) was added at room temperature. The reaction mixture was stirred for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (3 mL) and TFA (1 mL). The reaction mixture was stirred for 1 hour at room temperature and the solvent was removed in vacuo to give crude Compound X which was used directly without further purification.
실시예 25Example 25
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid methyl ester
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AB)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 25(45 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.93-8.06(m, 3H), 7.79(d, 1H), 7.64-7.75(m, 2H), 7.45(m, 1H), 7.25(m, 1H), 7.08(m, 1H), 6.19(s, 1H), 4.22(d, 1H), 3.95-4.15(m, 4H), 3.53-3.66(m, 4H), 3.29(d, 1H), 3.09(d, 2H), 3.03-3.17(m, 2H), 2.50-2.63(m, 1H), 2.35(br. s., 1H). MS: 계산치 625(MH+), 측정치 625(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] benzoic acid (compound AB). Example 25 (45 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.93-8.06 (m , 3H), 7.79 (d, 1H), 7.64-7.75 (m, 2H), 7.45 (m, 1H), 7.25 (m, 1H), 7.08 (m, IH), 6.19 (s, IH), 4.22 (d, IH), 3.95-4.15 (m, 4H), 3.53-3.66 (d, 2H), 3.03-3.17 (m, 2H), 2.50-2.63 (m, 1H), 2.35 (br. MS: Calculated 625 (MH < + >), found 625 (MH < + & gt ; ).
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AB)의 제조Preparation of 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2- yl] benzoic acid (compound AB)
단계 1: 다이옥산(6 mL) 중 t-부틸(8aR)-3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-카복실레이트(화합물 M, 200 mg, 0.83 mmol), 잔트포스(46 mg, 0.08 mmol), Cs2CO3(378 mg, 1.16 mmol), Pd(OAc)2(18 mg, 0.08 mmol) 및 4-요오도-벤조산 메틸 에스터(282 mg, 1.08 mmol)의 혼합물을 아르곤 대기로 3회 탈기하였다. 혼합물을 실온에서 5 분 동안 아르곤 대기하에 교반한 후, 90℃에서 밤새 가열하였다. 혼합물을 EtOAc(20 mL)로 희석하고, 셀라이트를 통해 여과하였다. 여액을 농축하고, 실리카 겔로 정제하여 화합물 AC(240 mg)를 수득하였다. Step 1 : To a solution of t- butyl (8aR) -3-oxo-1,2,5,6,8,8a-hexahydroimidazo [1,5- a] pyrazine-7- compound M, 200 mg, 0.83 mmol) , janteu phosphine (46 mg, 0.08 mmol), Cs 2 CO 3 (378 mg, 1.16 mmol), Pd (OAc) 2 (18 mg, 0.08 mmol) and 4-iodo- Benzoic acid methyl ester (282 mg, 1.08 mmol) was degassed three times with argon atmosphere. The mixture was stirred at room temperature for 5 minutes under an argon atmosphere and then heated at 90 < 0 > C overnight. The mixture was diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated and purified by silica gel to obtain compound AC (240 mg).
단계 2: THF(3 mL) 중 화합물 AC(240 mg, 0.64 mmol)의 용액에 실온에서 H2O(1 mL) 중 LiOHㆍH2O(215 mg, 5.10 mmol)의 용액을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반한 후, 이를 0℃에서 1 N HCl로 pH 3 내지 4로 산성화하였다. 이어서, 혼합물을 농축하고, 톨루엔으로 공비 건조하여 화합물 AD(231 mg)를 수득하고, 이를 다음 단계에서 추가 정제 없이 직접 사용하였다. Step 2 : To a solution of compound AC (240 mg, 0.64 mmol) in THF (3 mL) was added a solution of LiOH.H 2 O (215 mg, 5.10 mmol) in H 2 O (1 mL) at room temperature. The reaction mixture was stirred overnight at room temperature and then acidified to pH 3-4 with 1 N HCl at 0 < 0 > C. The mixture was then concentrated and azeotropically dried in toluene to give compound AD (231 mg) which was used directly in the next step without further purification.
단계 3: 다이클로로메탄(2 mL) 중 화합물 AD(231 mg, 0.64 mmol)의 용액에 실온에서 TFA(2 mL)를 첨가하였다. 혼합물을 실온에서 1 시간 동안 교반한 후, 농축하여 메틸 4-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)벤조산(화합물 AB)(240 mg)을 수득하였다. Step 3 : To a solution of compound AD (231 mg, 0.64 mmol) in dichloromethane (2 mL) was added TFA (2 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and then concentrated to give methyl 4- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- Benzoic acid (compound AB) (240 mg).
실시예 26Example 26
(R)-6-[(S)-2-(4-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(R) -6- [(S) -2- (4-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
2-클로로-4-플루오로벤즈알데하이드 및 메틸 아세토아세테이트 대신에 2-클로로-3-플루오로벤즈알데하이드 및 에틸 아세토아세테이트를 사용하여 실시예 25와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 26(76 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.85-7.96(m, 3H), 7.79(d, 1H), 7.61(d, 2H), 7.23-7.30(m, 2H), 7.08-7.19(m, 1H), 6.16(s, 1H), 4.62(d, 1H), 4.43(d, 1H), 4.22(m, 1H), 4.02-4.16(m, 2H), 3.97(m, 2H), 3.57-3.73(m, 3H), 3.36-3.49(m, 1H), 3.02-3.16(m, 2H), 0.95-1.08(m, 3H). MS: 계산치 639(MH+), 측정치 639(MH+).The title compound was prepared in analogy to example 25 using 2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate. Example 26 (76 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.85-7.96 (m , 3H), 7.79 (d, 1H), 7.61 (d, 2H), 7.23-7.30 (m, 2H), 7.08-7.19 ( (m, 2H), 3.97 (m, 2H), 3.57 (d, IH) -3.73 (m, 3H), 3.36-3.49 (m, 1H), 3.02-3.16 (m, 2H), 0.95-1.08 (m, 3H). MS: Calculated 639 (MH < + & gt ; ), Found 639 (MH & lt ; + & gt ; ).
실시예 27Example 27
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AB) 대신에 2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AE)을 사용하여 실시예 25와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 27(20 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.11(s, 1H), 7.90(d, 1H), 7.75-7.82(m, 2H), 7.66(d, 1H), 7.37(m, 1H), 7.23-7.29(m, 2H), 7.07-7.17(m, 1H), 6.16(s, 1H), 4.59(d, 1H), 4.34-4.45(m, 1H), 4.15-4.25(m, 1H), 4.01-4.13(m, 2H), 3.97(m, 2H), 3.52-3.67(m, 3H), 3.36-3.46(m, 1H), 3.02-3.16(m, 2H), 1.01(m, 3H). MS: 계산치 639(MH+), 측정치 639(MH+).4-fluorobenzaldehyde, methyl acetoacetate and 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazine Chloro-3-fluorobenzaldehyde, ethyl acetoacetate and 3 - [(8aS) -3-oxo-1,5,6,7,8,8a- The title compound was prepared in analogy to example 25 using hexahydroimidazo [l, 5-a] pyrazin-2-yl] benzoic acid (compound AE). Example 27 (20 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.11 (s , 1H), 7.90 (d, 1H), 7.75-7.82 (m, 2H), 7.66 (d, 1H), 7.37 (m, 1H) 1H), 4.15-4.25 (m, IH), 7.23-7.29 (m, 2H), 7.07-7.17 (M, 2H), 3.97 (m, 2H), 3.52-3.67 (m, 3H), 3.36-3.46 . MS: Calculated 639 (MH < + & gt ; ), Found 639 (MH & lt ; + & gt ; ).
3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AE)의 제조Preparation of 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2- yl] benzoic acid (Compound AE)
4-요오도-벤조산 메틸 에스터 대신에 3-요오도-벤조산 메틸 에스터를 사용하여 실시예 25의 화합물 AB와 유사하게 화합물 AE를 제조하였다.Compound AE was prepared analogously to compound AB of Example 25 using 3-iodo-benzoic acid methyl ester instead of 4-iodo-benzoic acid methyl ester.
실시예 28Example 28
(R)-6-[(S)-2-(2-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(2-carboxy-phenyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin-7-ylmethyl] -4- (2- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AB) 대신에 2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AF)을 사용하여 실시예 25와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 28(95 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.83-7.93(m, 2H), 7.80(d, 1H), 7.53(m, 1H), 7.24-7.35(m, 4H), 7.08-7.19(m, 1H), 6.16(s, 1H), 4.66(d, 1H), 4.48(d, 1H), 4.20-4.29(m, 1H), 4.06-4.11(m, 1H), 3.92-4.04(m, 3H), 3.65(d, 2H), 3.29-3.55(m, 3H), 3.13(m, 1H), 1.02(m, 3H). MS: 계산치 639(MH+), 측정치 639(MH+).4-fluorobenzaldehyde, methyl acetoacetate and 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazine Chloro-3-fluorobenzaldehyde, ethyl acetoacetate and 2 - [(8aS) -3-oxo-1,5,6,7,8,8a- Hexahydroimidazo [l, 5-a] pyrazin-2-yl] benzoic acid (Compound AF) the title compound was prepared in analogy to example 25. < Example 28 (95 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.83-7.93 (m , 2H), 7.80 (d, 1H), 7.53 (m, 1H), 7.24-7.35 (m, 4H), 7.08-7.19 ( (m, IH), 6.16 (s, IH), 4.66 (d, IH), 4.48 (d, IH), 4.20-4.29 3H), 3.65 (d, 2H), 3.29-3.55 (m, 3H), 3.13 (m, 1H), 1.02 (m, 3H). MS: Calculated 639 (MH < + & gt ; ), Found 639 (MH & lt ; + & gt ; ).
2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AF)의 제조Preparation of 2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] benzoic acid (Compound AF)
4-요오도-벤조산 메틸 에스터 대신에 2-요오도-벤조산 메틸 에스터를 사용하여 실시예 25의 화합물 AB와 유사하게 표제 화합물을 제조하였다.The title compound was prepared in analogy to compound AB of Example 25 using 2-iodo-benzoic acid methyl ester instead of 4-iodo-benzoic acid methyl ester.
실시예 29Example 29
(R)-6-[(S)-2-(3-카복시-페닐)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(R) -6- [(S) -2- (3-carboxy-phenyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid methyl ester
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AB) 대신에 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AE)을 사용하여 실시예 25와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 29(220 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.20-8.26(m, 1H), 8.03(d, 1H), 7.85-7.96(m, 2H), 7.78(m, 1H), 7.56(m, 1H), 7.49(m, 1H), 7.30(m, 1H), 7.13(m, 1H), 6.21(s, 1H), 4.78(d, 1H), 4.55-4.63(m, 1H), 4.36(dm, 1H), 4.13-4.29(m, 2H), 3.72-3.90(m, 3H), 3.65(s, 3H), 3.51-3.61(m, 1H), 3.35-3.40(m, 1H), 3.26-3.31(m, 1H). MS: 계산치 625(MH+), 측정치 625(MH+).(Compound AB) instead of 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- (8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] benzoic acid (Compound AE) The title compound was prepared. Example 29 (220 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.20-8.26 (m , 1H), 8.03 (d, 1H), 7.85-7.96 (m, 2H), 7.78 (m, 1H), 7.56 (m, (M, 1H), 7.49 (m, 1H), 7.30 (m, 1H), 7.13 (M, 2H), 3.72-3.90 (m, 3H), 3.65 (s, 3H), 3.51-3.61 (m, 1H). MS: Calculated 625 (MH < + & gt ; ), found 625 (MH < + & gt ; ).
실시예 30Example 30
2-[7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-1,5,6,8-테트라하이드로이미다조[1,5-a]피라진-8a-일]아세트산2- [7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -2-cyclopropyl-3-oxo-1,5,6,8-tetrahydroimidazo [1,5- a] pyrazin-
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AG)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 30(48 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.93(d, J = 3.0 Hz, 1H), 7.73(d, J = 3.0 Hz, 1H), 7.43(dd, J = 6.1, 8.7 Hz, 1H), 7.24(dd, J = 2.5, 8.8 Hz, 1H), 7.06(d, J = 2.8 Hz, 1H), 6.16(s, 1H), 4.14(d, J = 16.6 Hz, 1H), 3.85-3.71(m, 2H), 3.60(s, 3H), 3.46(d, J = 9.8 Hz, 1H), 3.30-3.15(m, 3H), 3.06(d, J = 11.3 Hz, 1H), 2.95-2.82(m, 2H), 2.45(d, J = 5.0 Hz, 1H), 2.39-2.29(m, 1H), 2.22(d, J = 11.5 Hz, 1H), 0.83-0.53(m, 4H). MS: 계산치 604(MH+), 측정치 604(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] benzoic acid (compound AG). Example 30 (48 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.93 (d , J = 3.0 Hz, 1H), 7.73 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 6.1, 8.7 Hz, 1H ), 7.24 (dd, J = 2.5, 8.8 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.16 (s, 1H), 4.14 (d, J = 16.6 Hz, 1H), 3.85-3.71 (m, 2H), 3.60 ( s, 3H), 3.46 (d, J = 9.8 Hz, 1H), 3.30-3.15 (m, 3H), 3.06 (d, J = 11.3 Hz, 1H), 2.95-2.82 ( 2H), 2.45 (d , J = 5.0 Hz, 1H), 2.39-2.29 (m, 1H), 2.22 (d , J = 11.5 Hz, 1H), 0.83-0.53 (m, 4H). MS: Calcd. 604 (MH + ), Measurement 604 (MH + ).
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AG)의 제조Preparation of 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] benzoic acid (Compound AG)
단계 1: 다이클로로메탄(250 mL) 중 피페라진-1,3-다이카복실산 1-t-부틸 에스터 3-메틸 에스터(10.6 g, 43 mmol)의 용액에 0℃에서 (Boc)2O(19 g, 86 mmol)를 첨가하였다. 반응 혼합물을 4 시간 동안 실온에서 교반한 후, 물로 급랭하고, 이어서 다이클로로메탄으로 추출하였다. 유기 층을 무수 Na2SO4로 건조한 후, 여액을 농축하였다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하여 화합물 AH(13.6 g, 수율 92%)를 수득하였다. Step 1: dichloromethane (250 mL) of the piperazine-1,3-dicarboxylic acid 1- t- butyl ester 3-methyl ester (10.6 g, 43 mmol) 2 O (19 eseo 0 ℃ (Boc) To a solution of g, 86 mmol). The reaction mixture was stirred at room temperature for 4 hours, then quenched with water and then extracted with dichloromethane. The organic layer was dried over anhydrous Na 2 SO 4 and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain Compound AH (13.6 g, yield 92%).
단계 2: 무수 THF(200 mL) 중 화합물 AH(13.4g, 38.9 mmol)의 용액에 -78℃에서 갓 제조한 LDA(THF 중 2 M, 38 mL)를 첨가하였다. 반응 혼합물을 -78℃에서 30 분 동안 교반한 후 실온으로 30 분 동안 가온하였다. 혼합물을 -78℃로 냉각하고, THF(10 mL) 중 알릴 브로마이드(6.7 mL, 77.9 mmol)의 용액을 첨가하였다. 혼합물을 실온으로 가온하고 밤새 교반한 후, 용매를 감압하에 제거하였다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하여 화합물 AI(13.6 g, 수율 91%)를 수득하였다. Step 2: To a solution of compound AH (13.4 g, 38.9 mmol) in anhydrous THF (200 mL) was added freshly prepared LDA (2 M in THF, 38 mL) at -78 < The reaction mixture was stirred at -78 < 0 > C for 30 min and then allowed to warm to room temperature for 30 min. The mixture was cooled to -78 C and a solution of allyl bromide (6.7 mL, 77.9 mmol) in THF (10 mL) was added. The mixture was warmed to room temperature and stirred overnight, then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain Compound AI (13.6 g, yield 91%).
단계 3: 무수 THF(20 mL) 중 화합물 AI(1.0 g, 2.6 mmol)의 용액에 -78℃에서 LAH(THF 중 2 M, 1.3 mL)를 첨가하였다. 반응 혼합물을 -78℃에서 30 분 동안 교반한 후 실온으로 가온하고 밤새 교반하였다. 무수 Na2SO4를 첨가하였다. 1 시간 후, 여액을 농축하였다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하여 화합물 AJ(0.7 g, 수율 75%)를 수득하였다. Step 3: To a solution of compound AI (1.0 g, 2.6 mmol) in anhydrous THF (20 mL) was added LAH (2 M in THF, 1.3 mL) at -78 < The reaction mixture was stirred at -78 < 0 > C for 30 min, then warmed to room temperature and stirred overnight. Anhydrous Na 2 SO 4 was added. After 1 h, the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain Compound AJ (0.7 g, yield 75%).
단계 4: 무수 다이클로로메탄(50 mL) 중 화합물 AJ(3 g, 8.4 mmol)의 용액에 0℃에서 데스-마틴 페리오디난(6 g, 14.1 mmol)을 첨가하였다. 반응 혼합물을 2 시간 동안 실온에서 교반한 후, 물로 급랭하였다. 여액을 다이클로로메탄으로 추출한 후, 무수 Na2SO4로 건조하고, 여액을 농축하여 추가 정제 없이 화합물 AK를 수득하였다. Step 4: To a solution of compound AJ (3 g, 8.4 mmol) in anhydrous dichloromethane (50 mL) at 0 C was added des-Martin ferriodin (6 g, 14.1 mmol). The reaction mixture was stirred at room temperature for 2 hours and then quenched with water. Extract the filtrate with dichloromethane, dried over anhydrous Na 2 SO 4 and concentrated the filtrate to give the compound AK without further purification.
단계 5: 다이클로로메탄(15 mL) 중 화합물 AK(1.5 g, 4.2 mmol)의 교반된 용액에 연속하여 아세트산 및 사이클로프로필아민(0.29 mL, 4.2 mmol)을 첨가하였다. 반응 혼합물을 2 시간 동안 실온에서 교반한 후, 나트륨 트라이아세톡시보로하이드라이드(520 mg, 8.4 mmol)를 첨가하고, 반응 혼합물을 실온에서 3 시간 동안 교반하였다. 반응 혼합물을 포화 NH4Cl로 급랭하였다. 이어서, 물(20 mL)을 첨가한 후 다이클로로메탄(40 mL)을 첨가하였다. 유기 층을 분리한 후 염수로 세척한 후 Na2SO4로 건조하였다. 여액을 농축하여 추가 정제 없이 화합물 AL을 수득하였다. Step 5: To a stirred solution of compound AK (1.5 g, 4.2 mmol) in dichloromethane (15 mL) was successively added acetic acid and cyclopropylamine (0.29 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (520 mg, 8.4 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated NH 4 Cl. Water (20 mL) was then added followed by dichloromethane (40 mL). The organic layer was separated, washed with brine, and dried over Na 2 SO 4 . The filtrate was concentrated to give compound AL without further purification.
단계 6: 무수 THF(20 mL) 중 화합물 AL(1.5 g, 3.8 mmol)의 용액에 0℃에서 NaH(0.26 g, 9.4 mmol)를 첨가하였다. 반응 혼합물을 85℃에서 밤새 교반하였다. 이어서, 반응 생성물을 실온으로 냉각하고, 물로 급랭하고 다이클로로메탄으로 추출하였다. 유기 층을 무수 Na2SO4로 건조한 후 진공에서 농축하였다. 잔사를 실리카 겔 컬럼 크로마토그래피로 정제하여 화합물 AM(1.0 g, 수율 82%)을 수득하였다. Step 6: To a solution of compound AL (1.5 g, 3.8 mmol) in anhydrous THF (20 mL) was added NaH (0.26 g, 9.4 mmol) at 0 ° C. The reaction mixture was stirred at 85 < 0 > C overnight. The reaction product was then cooled to room temperature, quenched with water and extracted with dichloromethane. After drying the organic layer over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain compound AM (1.0 g, yield 82%).
단계 7: 질소 대기하에 H2O(1 mL) 및 CH3CN(6 mL) 중 화합물 AM(700 mg, 2.2 mmol)의 용액에 RuCl3ㆍH2O(18 mg, 0.086 mmol)을 첨가한 후, NaIO4(2.7 g, 12.6 mmol)를 첨가하였다. 반응 생성물을 실온에서 밤새 교반하였다. 혼합물을 물 및 에틸 에터로 희석하고, 셀라이트 패드를 통해 여과하고, 상기 패드를 에틸 에터로 세척하였다. 수층을 다이클로로메탄으로 추출하였다. 합한 유기 층을 Na2SO4로 건조하고 농축하여 화합물 AN(450 mg, 수율 60%)을 수득하였다. Step 7: To a solution of compound AM (700 mg, 2.2 mmol) in H 2 O (1 mL) and CH 3 CN (6 mL) under nitrogen atmosphere was added RuCl 3 .H 2 O (18 mg, 0.086 mmol) then, it was added NaIO 4 (2.7 g, 12.6 mmol ). The reaction product was stirred overnight at room temperature. The mixture was diluted with water and ethyl ether, filtered through a celite pad, and the pad was washed with ethyl ether. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na 2 SO 4 and concentrated to give compound AN (450 mg, yield 60%).
단계 8: 다이클로로메탄(8 mL) 중 화합물 AN(600 mg, 1.76 mmol)의 용액에 0℃에서 TFA(2 mL)를 첨가하였다. 반응 혼합물을 2 시간 동안 실온에서 교반한 후, 이를 농축하여 추가 정제 없이 화합물 AG를 수득하였다. Step 8: To a solution of compound AN (600 mg, 1.76 mmol) in dichloromethane (8 mL) at 0 C was added TFA (2 mL). The reaction mixture was stirred for 2 hours at room temperature and then concentrated to give compound AG without further purification.
실시예 31Example 31
2-[7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-1,5,6,8-테트라하이드로이미다조[1,5-a]피라진-8a-일]아세트산2- [7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -2-isopropyl-3-oxo-1,5,6,8-tetrahydroimidazo [1,5- a] pyrazin-
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]벤조산(화합물 AG) 대신에 2-(2-이소프로필-3-옥소-5,6,7,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-일)아세트산(화합물 AO)을 사용하여 실시예 30과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 31(8 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.94(d, J = 3.0 Hz, 1H), 7.73(d, J = 3.3 Hz, 1H), 7.43(dd, J = 6.0, 8.8 Hz, 1H), 7.24(dd, J = 2.8, 8.8 Hz, 1H), 7.11-7.02(m, 1H), 6.16(s, 1H), 4.18-4.04(m, 2H), 3.79(d, J = 16.6 Hz, 2H), 3.61(s, 3H), 3.47(d, J = 9.5 Hz, 1H), 3.29-3.24(m, 1H), 3.20(d, J = 9.5 Hz, 1H), 3.09(d, J = 11.5 Hz, 1H), 2.90(d, J = 15.6 Hz, 2H), 2.38-2.12(m, 3H), 1.18(d, J = 7.0 Hz, 3H), 1.12(d, J = 6.8 Hz, 3H). MS: 계산치 606(MH+), 측정치 606(MH+).(Compound A) instead of 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- Similar to Example 30, using 2-isopropyl-3-oxo-5,6,7,8-tetrahydro-1H-imidazo [1,5- a] pyrazin-8a-yl) acetic acid (Compound AO) The title compound was prepared. Example 31 (8 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.94 (d , J = 3.0 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.43 (dd, J = 6.0, 8.8 Hz, 1H 2H), 3.79 (d , J = 16.6 Hz, 1H), 7.24 (dd , J = 2.8,8.8 Hz, 1H), 7.11-7.02 (m, 2H), 3.61 (s, 3H ), 3.47 (d, J = 9.5 Hz, 1H), 3.29-3.24 (m, 1H), 3.20 (d, J = 9.5 Hz, 1H), 3.09 (d, J = 11.5 Hz, 1H), 2.90 (d , J = 15.6 Hz, 2H), 2.38-2.12 (m, 3H), 1.18 (d , J = 7.0 Hz, 3H), 1.12 (d , J = 6.8 Hz, 3H). MS: Calculated 606 (MH < + & gt ; ), found 606 (MH < + & gt ; ).
2-(2-이소프로필-3-옥소-5,6,7,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-일)아세트산(화합물 AO)의 제조Preparation of 2- (2-isopropyl-3-oxo-5,6,7,8-tetrahydro-1H-imidazo [1,5- a] pyrazin-8a-yl) acetic acid (Compound AO)
사이클로프로필 아민 대신에 이소-프로필 아민을 사용하여 실시예 30의 화합물 AG와 유사하게 표제 화합물을 제조하였다.The title compound was prepared in analogy to example 30, compound AG using iso-propylamine instead of cyclopropylamine.
실시예 32Example 32
(R)-6-[(S)-2-(1-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-ylmethyl] -4 2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 2-아미노-2-메틸-프로판오에이트 하이드로클로라이드 염을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 32(60 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98(d, 1H), 7.79(d, 1H), 7.23-7.38(m, 2H), 7.09-7.23(m, 1H), 6.25(s, 1H), 4.23(br. s., 1H), 4.06(m, 3H), 3.78-3.97(m, 2H), 3.59-3.71(m, 1H), 3.14-3.29(m, 2H), 2.89-3.14(m, 2H), 2.54(br. s., 2H), 1.40-1.57(m, 6H), 1.04-1.19(m, 3H). MS: 계산치 605(MH+), 측정치 605(MH+).The title compound was prepared in analogy to example 19 using methyl 2-amino-2-methyl-propanoate hydrochloride salt instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. Example 32 (60 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98 (d , 1H), 7.79 (d, 1H), 7.23-7.38 (m, 2H), 7.09-7.23 (m, 1H), 6.25 (s, 2H), 3.14-3.29 (m, 2H), 2.89-3.14 (m, 2H), 4.23 (m, (m, 2H), 2.54 (br.s, 2H), 1.40-1.57 (m, 6H), 1.04-1.19 (m, 3H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
실시예 33Example 33
3-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carbonic acid
2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q) 대신에 2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산(화합물 AP)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 33(381 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.90-7.91(d, J = 4.0 Hz, 1H), 7.55(m, 1H), 7.29(m, 1H), 7.13(m, 1H), 6.20(s, 1H), 4.76(d, J = 16.0 Hz, 1H), 4.60(d, J = 16.0 Hz, 1H), 4.12(m, 1H), 4.02-4.06(m, 1H), 3.70-3.80(m, 3H), 3.65(s, 3H), 3.32-3.44(m, 2H), 3.20(m, 2H), 3.09-3.05(d, J = 16.0 Hz, 1H), 2.79-2.83(d, J = 16.0 Hz, 1H), 1.47(s, 6H). MS: 계산치 605(MH+), 측정치 605(MH+).2-chloro-3-fluorobenzaldehyde, ethyl acetoacetate and 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazine Chloro-4-fluorobenzaldehyde, methyl acetoacetate and 3 - [(8aS) -3-oxo-1,5-dihydro- The title compound was prepared in analogy to example 19, using 6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] Respectively. Example 33 (381 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.90-7.91 (d, J = 4.0 Hz, 1H), 7.55 (m, 1H), 7.29 (m, 1H), 7.13 ( m, 1H), 6.20 (s, 1H), 4.76 (d, J = 16.0 Hz, 1H), 4.60 (d, J = 16.0 Hz, 1H), 4.12 (m, 1H) 2H), 3.09-3.05 (d , J = 8 Hz), 4.02-4.06 (m, 1H), 3.70-3.80 (m, 3H) 16.0 Hz, 1H), 2.79-2.83 (d , J = 16.0 Hz, 1H), 1.47 (s, 6H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산(화합물 AP)의 제조3-methyl-butanoic acid (compound AP (5-a) pyrazin-2-yl] )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 3-아미노-3-메틸-부탄오에이트 하이드로클로라이드 염(화합물 AP-1)을 사용하여 실시예 19의 화합물 Q와 유사하게 표제 화합물을 제조하였다.(Compound AP-1) was used instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt to obtain Compound Q of Example 19 , The title compound was prepared.
메틸 3-아미노-3-메틸-부탄오에이트 하이드로클로라이드 염(화합물 AP-1)의 제조Preparation of methyl 3-amino-3-methyl-butaneoate hydrochloride salt (compound AP-1)
DL-3-아미노이소부티르산 대신에 3-아미노-3-메틸-부티르산을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 AP-1을 제조하였다.Compound AP-1 was prepared similarly to compound 20 of Example 20 using 3-amino-3-methyl-butyric acid instead of DL-3-aminoisobutyric acid.
실시예 34Example 34
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carbonic acid
3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q) 대신에 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산(화합물 AP)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 34(26 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.99-8.00(d, J = 4.0 Hz, 1H), 7.83- 7.84(d, J = 4.0 Hz, 1H), 7.35(m, 2H), 7.20(m, 1H), 6.25(s, 1H), 4.20-4.40(m, 2H), 4.10(m, 2H), 3.94(m, 2H), 3.70(m, 2H), 3.29(m, 5H), 3.02-3.06(d, J = 16.0 Hz, 1H), 2.80-2.84(d, J = 16.0 Hz, 1H), 1.46(s, 6H), 1.11-1.15(t, J 1 = 8.0 Hz, J 2 = 16.0 Hz, 3H). MS: 계산치 619(MH+), 측정치 619(MH+).3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] -2,2-dimethyl- (Compound Q) instead of 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- -Butanoic acid (compound AP), the title compound was prepared in analogy to example 19. < RTI ID = 0.0 > Example 34 (26 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.99-8.00 (d , J = 4.0 Hz, 1H), 7.83- 7.84 (d, J = 4.0 Hz, 1H), 7.35 (m, 2H), 7.20 2H), 3.94 (m, 2H), 3.70 (m, 2H), 3.29 (m, 5H) 3.02-3.06 (d, J = 16.0 Hz , 1H), 2.80-2.84 (d, J = 16.0 Hz, 1H), 1.46 (s, 6H), 1.11-1.15 (t, J 1 = 8.0 Hz, J 2 = 16.0 Hz, 3H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
실시예 35Example 35
1-[[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산1 - [[(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid
2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 메틸 1-(아미노메틸)사이클로프로판카복실레이트 하이드로클로라이드 염(화합물 AQ)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 35(760 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.90-7.91(d, J = 4.0 Hz, 1H), 7.55(m, 1H), 7.29(m, 1H), 7.13(m, 1H), 6.20(s, 1H), 4.77(d, J = 16.0 Hz, 1H), 4.59(d, J = 16.0 Hz, 1H), 4.19(m, 1H), 4.07-4.10(m, 1H), 3.73-3.77(m, 3H), 3.65(s, 3H), 3.36-3.50(m, 4H), 3.15-3.24(m, 2 H), 1.29(m, 2H), 1.02(m, 2H). MS: 계산치 603(MH+), 측정치 603(MH+).Chloro-3-fluorobenzaldehyde, ethyl acetoacetate and ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt in place of 2-chloro-4-fluorobenzaldehyde, The title compound was prepared in analogy to example 19 using methyl 1- (aminomethyl) cyclopropanecarboxylate hydrochloride salt (compound AQ). Example 35 (760 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.90-7.91 (d, J = 4.0 Hz, 1H), 7.55 (m, 1H), 7.29 (m, 1H), 7.13 ( m, 1H), 6.20 (s, 1H), 4.77 (d, J = 16.0 Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 4.19 (m, 1H) 3H), 3.36-3.50 (m, 4H), 3.15-3.24 (m, 2H), 1.29 (m, 2H) ), 1.02 (m, 2H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
메틸 1-(아미노메틸)사이클로프로판카복실레이트 하이드로클로라이드 염(화합물 AQ)의 제조Preparation of methyl 1- (aminomethyl) cyclopropanecarboxylate hydrochloride salt (Compound AQ)
DL-3-아미노이소부티르산 대신에 1-(아미노메틸)사이클로프로판카복실산(CAS 번호: 139132-50-6, 제이 앤드 케이(J&K); 이의 합성을 위해 문헌[Mertin A., et al., Synlett, 1991, 2, 87-9]을 참조한다)을 사용하여 실시예 20의 화합물 W와 유사하게 표제 화합물을 제조하였다.(Mertin A., et al., Synlett ) for the synthesis of 1- (aminomethyl) cyclopropanecarboxylic acid (CAS number: 139132-50-6, J & K) instead of DL-3-aminoisobutyric acid , 1991, 2, 87-9), the title compound was prepared.
실시예 36Example 36
1-[[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4 -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 1-(아미노메틸)사이클로프로판카복실레이트 하이드로클로라이드 염(화합물 AQ)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 36(170 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.92-7.91(d, J = 4.0 Hz, 1H), 7.38(m, 2H), 7.26(m, 1H), 6.27(s, 1H), 4.77(d, J = 16.0 Hz, 1H), 4.59(d, J = 16.0 Hz, 1H), 4.11(m, 1H), 4.07-4.10(m, 3H), 3.72-3.78(m, 3H), 3.36-3.47(m, 4H), 3.15-3.24(m, 2 H), 1.29(m, 2H), 1.13(t, J 1 =8.0 Hz, J 2 =16.0 Hz, 3H), 1.02(m, 2H). MS: 계산치 617(MH+), 측정치 617(MH+).The title compound was prepared in analogy to example 19 using methyl 1- (aminomethyl) cyclopropanecarboxylate hydrochloride salt (compound AQ) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt . Example 36 (170 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.92-7.91 (d, J = 4.0 Hz, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.27 ( s, 1H), 4.77 (d, J = 16.0 Hz, 1H), 4.59 (d, J = 16.0 Hz, 1H), 4.11 (m, 1H), 4.07-4.10 (m, 2H), 1.29 (m, 2H), 1.13 (t, J 1 = 8.0 Hz, J 2 = 16.0 Hz, 3H), 1.02 (m, 2H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
실시예 37Example 37
1-[[(8aS)-7-[[(4S)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산1 - [[(8aS) -7 - [[(4S) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2- yl] methyl] cyclopropanecarboxylic acid
2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q) 대신에 2-메틸-3,4-다이플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3-메틸-부탄산(화합물 AP)을 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 37(153 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.90-7.91(d, J = 4.0 Hz, 1H), 7.26(m, 1H), 7.10(m, 1H), 5.95(s, 1H), 4.74(d, J = 16.0 Hz, 1H), 4.57(d, J = 16.0 Hz, 1H), 4.10(m, 2H), 3.70-3.80(m, 3H), 3.66(s, 3H), 3.36-3.42(m, 2H), 3.20(m, 2H), 3.09-3.05(d, J = 16.0 Hz, 1H), 2.79-2.83(d, J = 16.0 Hz, 1H), 2.53(s, 3H), 1.47(s, 6H). MS: 계산치 603(MH+), 측정치 603(MH+).2-chloro-3-fluorobenzaldehyde, ethyl acetoacetate and 3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazine Methyl-3,4-difluorobenzaldehyde, methyl acetoacetate and 3 - [(8aS) -3-oxo-pyridin- The title compound was prepared in analogy to example 19, using 1, 5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] Lt; / RTI > Example 37 (153 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.90-7.91 (d, J = 4.0 Hz, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 5.95 ( s, 1H), 4.74 (d, J = 16.0 Hz, 1H), 4.57 (d, J = 16.0 Hz, 1H), 4.10 (m, 2H), 3.70-3.80 (m, 3H), 3.66 (s, 3H ), 3.36-3.42 (m, 2H), 3.20 (m, 2H), 3.09-3.05 (d, J = 16.0 Hz, 1H), 2.79-2.83 (d, J = 16.0 Hz , ≪ / RTI > 1H), 2.53 (s, 3H), 1.47 (s, 6H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
실시예 38Example 38
1-[[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로프로판카복실산Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-benzothiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopropanecarboxylic acid
2-클로로-4-플루오로벤즈알데하이드 대신에 2-메틸-3,4-다이플루오로벤즈알데하이드를 사용하여 실시예 35와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 38(54 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.90-7.91(d, J = 4.0 Hz, 1H), 7.26(m, 1H), 7.12(m, 1H), 5.95(s, 1H), 4.74(d, J = 16.0 Hz, 1H), 4.56(d, J = 16.0 Hz, 1H), 4.07-4.17(m, 2H), 3.70-3.77(m, 3H), 3.66(s, 3H), 3.35-3.46(m, 4H), 3.15-3.22(m, 2H), 2.51(s, 3H), 1.29(m, 2H), 1.02(m, 2H). MS: 계산치 601(MH+), 측정치 601(MH+).The title compound was prepared in analogy to example 35 using 2-methyl-3,4-difluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde. Example 38 (54 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.90-7.91 (d, J = 4.0 Hz, 1H), 7.26 (m, 1H), 7.12 (m, 1H), 5.95 (s, 1H), 4.74 (d , J = 16.0 Hz, 1H), 4.56 (d , J = 16.0 Hz, 1H), 4.07-4.17 2H), 1.02 (m, 2H), 2.50 (s, 3H), 3.69 (m, 2H) . MS: Calcd. 601 (MH + ), Measurement 601 (MH + ).
실시예 39Example 39
3-[(2S,8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로부탄카복실산Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2- yl] cyclobutanecarboxylic acid
2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 대신에 2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 메틸 트랜스-3-아미노-사이클로부탄카복실레이트 하이드로클로라이드(CAS 번호: 74316-29-3; 이의 합성을 위해 문헌[Grygorenko O. O., et al., Synthetic Communications, 2011, 41, 1644-1649]을 참조한다)를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 39(44 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(dd, J = 4.0, 3.3 Hz, 1H), 7.77(dd, J = 3.1, 1.4 Hz, 1H), 7.43(ddd, J = 8.7, 6.1, 2.5 Hz, 1H), 7.20 내지 7.28(m, 1H), 6.99-7.13(m, 1H), 6.18(s, 1H), 4.58-4.73(m, 1H), 4.11(dd, J = 16.9, 4.6 Hz, 1H), 3.73-3.97(m, 3H), 3.61(s, 3H), 2.82-3.28(m, 5H), 2.74(d, J = 11.8 Hz, 1H), 2.15-2.65 ppm(m, 6H). MS: 계산치 603(MH+), 측정치 603(MH+).Chloro-3-fluorobenzaldehyde, ethyl acetoacetate and ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride instead of 2-chloro-4-fluorobenzaldehyde, Trans - 3-amino-cyclobutanecarboxylate hydrochloride (CAS number: 74316-29-3; see Grygorenko OO, et al., Synthetic Communications, 2011, 41 , 1644-1649 for its synthesis) The title compound was prepared in analogy to example 19. < RTI ID = 0.0 > Example 39 (44 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (dd , J = 4.0, 3.3 Hz, 1H), 7.77 (dd, J = 3.1, 1.4 Hz, 1H), 7.43 (ddd, J = 8.7, 1H), 4.19 (dd , J = 16.9, < RTI ID = 0.0 > (M, 3H), 2.82-3.28 (m, 5H), 2.74 (d , J = 11.8Hz, 1H), 2.15-2.65ppm (m, 6H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
실시예 40Example 40
3-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로부탄카복실산4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] cyclobutanecarboxylic acid
2-클로로-3-플루오로벤즈알데하이드, 에틸 아세토아세테이트 및 에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 대신에 2-클로로-4-플루오로벤즈알데하이드, 메틸 아세토아세테이트 및 메틸 시스-3-아미노-사이클로부탄카복실레이트 하이드로클로라이드(CAS 번호: 1212304-86-3; 이의 합성을 위해 문헌[Grygorenko O. O., et al., Synthetic Communications, 2011, 41, 1644-1649]을 참조한다)를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 40(5 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.92-8.02(m, 1H), 7.77(dd, J = 3.1, 1.4 Hz, 1H), 7.38-7.48(m, 1H), 7.24(d, J = 6.3 Hz, 1H), 6.98-7.15(m, 1H), 6.18(s, 1H), 4.58-4.75(m, 1H), 4.04-4.19(m, 1H), 3.72-3.97(m, 3H), 3.61(s, 4H), 2.81-3.27(m, 6H), 2.33-2.63 ppm(m, 5H). MS: 계산치 603(MH+), 측정치 603(MH+).Chloro-3-fluorobenzaldehyde, ethyl acetoacetate and ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride instead of 2-chloro-4-fluorobenzaldehyde, Cis - 3-amino-cyclobutanecarboxylate hydrochloride (CAS number: 1212304-86-3; see Grygorenko OO, et al., Synthetic Communications, 2011, 41 , 1644-1649 for its synthesis) The title compound was prepared in analogy to example 19. < RTI ID = 0.0 > Example 40 (5 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.92-8.02 (m , 1H), 7.77 (dd, J = 3.1, 1.4 Hz, 1H), 7.38-7.48 (m, 1H), 7.24 (d, 1H, J = 6.3 Hz, 1H), 6.98-7.15 (m, IH), 6.18 (s, IH), 4.58-4.75 (m, , 3.61 (s, 4H), 2.81-3.27 (m, 6H), 2.33-2.63 ppm (m, 5H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
실시예 41Example 41
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산3-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
에틸 아세토아세테이트 대신에 메틸 아세토아세테이트를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 41(250 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.09-7.36(m, 3H), 6.23(s, 1H), 4.04-4.15(m, 1H), 3.78-3.98(m, 3H), 3.61(s, 3H), 3.36-3.55(m, 3H), 3.04-3.28(m, 2H), 2.76-2.99(m, 2H), 2.12-2.45(m, 2H), 1.15-1.25 ppm(m, 6H). MS: 계산치 605(MH+), 측정치 605(MH+).The title compound was prepared in analogy to example 19 using methyl acetoacetate instead of ethyl acetoacetate. Example 41 (250 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.09-7.36 (m, 3H), 6.23 (s 2H), 2.76-2.99 (m, 3H), 3.46-3.55 (m, 3H) (m, 2H), 2.12 - 2.45 (m, 2H), 1.15 - 1.25 ppm (m, 6H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
실시예 42Example 42
3-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
2-클로로-3-플루오로벤즈알데하이드 및 에틸 아세토아세테이트 대신에 2-클로로-4-플루오로벤즈알데하이드 및 메틸 아세토아세테이트를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 42(260 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.42(dd, J = 8.5, 6.0 Hz, 1H), 7.24(dd, J = 8.7, 2.6 Hz, 1H), 7.06(td, J = 8.4, 2.8 Hz, 1H), 6.17(s, 1H), 4.09(d, J = 16.8 Hz, 1H), 3.79-3.98(m, 3H), 3.61(s, 3H), 3.51(t, J = 8.9 Hz, 1H), 3.36-3.44(m, 1H), 3.04-3.26(m, 3H), 2.75-3.00(m, 2H), 2.11-2.43(m, 2H), 1.20 ppm(d, J = 3.0 Hz, 6H). MS: 계산치 605(MH+), 측정치 605(MH+).The title compound was prepared in analogy to example 19 using 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate instead of 2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 42 (260 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.42 (dd, J = 8.5, 6.0 Hz, 1H ), 7.24 (dd, J = 8.7, 2.6 Hz, 1H), 7.06 (td, J = 8.4, 2.8 Hz, 1H), 6.17 (s, 1H), 4.09 (d, J = 16.8 Hz, 1H), 3.79 (M, 3H), 3.61 (s, 3H), 3.51 (t , J = 8.9 Hz, 1H), 3.36-3.44 , 2H), 2.11-2.43 (m, 2H), 1.20 ppm (d , J = 3.0 Hz, 6H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
실시예 43Example 43
3-[(8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산Methyl-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-1 - [(4-fluoro- , 4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2-dimethyl-propanoic acid
2-클로로-3-플루오로벤즈알데하이드 및 에틸 아세토아세테이트 대신에 2-메틸-3,4-다이플루오로벤즈알데하이드 및 메틸 아세토아세테이트를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 43(110 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.3 Hz, 1H), 7.75(d, J = 3.3 Hz, 1H), 6.96-7.09(m, 2H), 5.93(s, 1H), 4.04-4.16(m, 1H), 3.78-3.98(m, 3H), 3.62(s, 3H), 3.36-3.56(m, 3H), 3.05-3.26(m, 2H), 2.74-2.97(m, 2H), 2.57(d, J = 2.3 Hz, 3H), 2.36(td, J = 11.7, 3.6 Hz, 1H), 2.18(t, J = 10.9 Hz, 1H), 1.20 ppm(d, J = 3.3 Hz, 6H). MS: 계산치 603(MH+), 측정치 603(MH+).The title compound was prepared in analogy to example 19 using 2-methyl-3,4-difluorobenzaldehyde and methyl acetoacetate instead of 2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 43 (110 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.3 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 6.96-7.09 (m, 2H), 5.93 (s 2H), 2.74-2.97 (m, 3H), 3.64-3.56 (m, 3H) (m, 2H), 2.57 ( d, J = 2.3 Hz, 3H), 2.36 (td, J = 11.7, 3.6 Hz, 1H), 2.18 (t, J = 10.9 Hz, 1H), 1.20 ppm (d, J = 3.3 Hz, 6H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
실시예 44Example 44
3-[(8aS)-7-[[(4S)-4-(3-플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산3 - [(8aS) -7 - [[(4S) -4- (3-fluoro- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
2-클로로-3-플루오로벤즈알데하이드 및 에틸 아세토아세테이트 대신에 2-메틸-3-플루오로벤즈알데하이드 및 메틸 아세토아세테이트를 사용하여 실시예 19와 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 44(74 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.0 Hz, 1H), 7.74(d, J = 3.3 Hz, 1H), 7.03-7.21(m, 2H), 6.88-6.99(m, 1H), 5.98(s, 1H), 4.03-4.17(m, 1H), 3.79-3.99(m, 4H), 3.62(s, 3H), 3.41-3.56(m, 2H), 3.07-3.26(m, 2H), 2.75-2.98(m, 2H), 2.53(d, J = 2.0 Hz, 3H), 2.29-2.45(m, 1H), 2.18(t, J = 11.2 Hz, 1H), 1.20 ppm(d, J = 3.3 Hz, 6H). MS: 계산치 585(MH+), 측정치 585(MH+).The title compound was prepared in analogy to example 19 using 2-methyl-3-fluorobenzaldehyde and methyl acetoacetate instead of 2-chloro-3-fluorobenzaldehyde and ethyl acetoacetate. Example 44 (74 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.0 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.03-7.21 (m, 2H), 6.88-6.99 (s, 3H), 3.41-3.56 (m, 2H), 3.07-3.26 (m, IH) (m, 2H), 2.75-2.98 ( m, 2H), 2.53 (d, J = 2.0 Hz, 3H), 2.29-2.45 (m, 1H), 2.18 (t, J = 11.2 Hz, 1H), 1.20 ppm (d , J = 3.3 Hz, 6H). MS: Calculated 585 (MH < + & gt ; ), found 585 (MH < + & gt ; ).
실시예 45Example 45
7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산Phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6- Methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-
실시예 45의 제조Preparation of Example 45
테트라하이드로푸란(1.5 mL) 중 메틸 7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실레이트(화합물 AQ, 150 mg, 0.25 mmol)의 용액에 물(1.5 mL) 중 리튬 하이드록사이드 일수화물(52 mg, 1.25 mmol)을 첨가하였다. 반응 혼합물을 실온에서 2 시간 동안 교반한 후, 이를 1 N 하이드로클로라이드 용액으로 pH 3.0으로 중성화하였다. 혼합물을 에틸 아세테이트(30 mL)로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조하고, 여과한 후 농축하였다. 잔사를 prep-HPLC로 정제하여 2개 부분입체이성질체의 혼합물로서 실시예 45(5 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.06-7.95(m, 1H), 7.87(s, 1H), 7.55-7.44(m, 1H), 7.32-7.23(m, 1H), 7.15-7.03(m, 1H), 6.18(s, 1H), 4.37-4.21(m, 1H), 4.09-3.91(m, 1H), 3.91-3.77(m, 2H), 3.62(d, J = 2.0 Hz, 4H), 3.52-3.39(m, 2H), 3.22-2.96(m, 2H), 2.75-2.58(m, 1H), 2.50-2.42(m, 1H), 0.74(d, J = 1.5 Hz, 4H). MS: 계산치 589(MH+), 측정치 589(MH+).To a solution of methyl 7 - [[(4R) -4- (2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine- (Compound AQ, 150 mg, 0.25 mmol) in THF (5 mL) was added lithium hydroxide monohydrate (52 mg, 1.25 mmol) in water (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours, then it was neutralized to pH 3.0 with 1 N hydrochloride solution. The mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried with Na 2 SO 4 and concentrated after filtration. The residue was purified by prep-HPLC to give Example 45 (5 mg) as a mixture of two diastereomers. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.06-7.95 (m , 1H), 7.87 (s, 1H), 7.55-7.44 (m, 1H), 7.32-7.23 (m, 1H), 7.15- 2H), 3.62 (d , J = 2.0 Hz, 1H), 7.03 (m, 1H), 6.18 (s, J = 1.5 Hz, 4H), 3.52-3.39 (m, 2H), 3.22-2.96 (m, 2H), 2.75-2.58 (m, . MS: Calculated 589 (MH < + & gt ; ), found 589 (MH < + & gt ; ).
7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실레이트(화합물 AQ)의 제조Phenyl) -5-methoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6- Methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylate (Compound AQ)
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 AR)를 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다.(Compound D) instead of methyl 2-cyclopropyl-3-oxo-1,5,6,7,8, 8a -Hexahydroimidazo [l, 5-a] pyrazine-8-carboxylate (compound AR), the title compound was prepared in analogy to example 1.
시스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 AR)의 제조Preparation of cis-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (compound AR)
단계 1: 테트라클로로메탄(150 mL) 중 다이메틸 말레에이트(7.2 g, 50 mmol)의 용액에 0℃에서 질소 대기하에 테트라클로로메탄(10 mL) 중 브롬(8.8 g, 55 mmol)을 적가하였다. 반응 혼합물을 0℃에서 밤새 교반하였다. 반응 혼합물을 빙수를 첨가하여 급랭한 후 Na2SO3 용액을 세척하였다. 유기 상을 물로 세척하고, 분리하고, Na2SO4로 건조한 후 농축하여 조질 화합물 AS(15.2 g)를 수득하였다. Step 1: To a solution of dimethyl maleate (7.2 g, 50 mmol) in tetrachloromethane (150 mL) was added bromine (8.8 g, 55 mmol) in tetrachloromethane (10 mL) . The reaction mixture was stirred overnight at 0 < 0 > C. The reaction mixture was quenched by the addition of ice-water and washed with Na 2 SO 3 solution. The organic phase was washed with water, separated and concentrated after drying with Na 2 SO 4 to give a crude compound AS (15.2 g).
단계 2: 벤젠(120 mL) 중 화합물 AS(10.6 g, 35 mmol)의 용액에 40℃에서 질소 대기하에 벤젠(20 mL) 중 N,N-다이벤질에틸렌다이아민(8.4 g, 35 mmol) 및 트라이에틸 아민(9.7, 70 mmol)을 적가하였다. 반응 혼합물을 10 분 동안 교반하고, 밤새 환류 가열하였다. 반응 혼합물을 빙수를 첨가하여 냉각한 후 석유 에터:에틸 아세테이트 = 10:1(50 mL)로 3회 추출하고, 합한 유기 상을 Na2SO4로 건조하고, 여과한 후 농축하였다. 잔사를 컬럼 크로마토그래피로 정제하여 화합물 AT(3.3 g)를 수득하였다. Step 2: To a solution of compound AS (10.6 g, 35 mmol) in benzene (120 mL) was added N, N -dibenzylethylenediamine (8.4 g, 35 mmol) in benzene Triethylamine (9.7, 70 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes and heated to reflux overnight. The reaction mixture was cooled by addition of ice-water petroleum ether: ethyl acetate = 10: 1 and extracted three times with 1 (50 mL) and dry the combined organic phases with Na 2 SO 4 and concentrated after filtration. The residue was purified by column chromatography to obtain compound AT (3.3 g).
단계 3: THF(60 mL) 중 화합물 AT(4.5 g, 11.8 mmol)의 용액에 다이-t-부틸 다이카보네이트 및 탄소상 팔라듐 하이드록사이드(1.0 g)를 첨가하였다. 반응 혼합물을 45℃로 밤새 수소 대기 압력하에 가열하였다. 반응 혼합물을 여과하고 농축하였다. 잔사를 컬럼 크로마토그래피로 정제하여 화합물 AU(3.6 g)를 수득하였다. Step 3: To a solution of compound AT (4.5 g, 11.8 mmol) in THF (60 mL) was added di- t- butyl dicarbonate and palladium hydroxide on carbon (1.0 g). The reaction mixture was heated to 45 < 0 > C overnight under hydrogen atmospheric pressure. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography to obtain Compound AU (3.6 g).
단계 4: 55℃에서 메탄올(4.0 mL) 중 화합물 AU(760 mg, 1.89 mmol)의 용액에 물(1 mL) 중 나트륨 하이드록사이드(98 mg, 2.46 mmol)를 적가하였다. 반응 혼합물을 55℃에서 2 시간 동안 교반하였다. 반응 혼합물을 냉각하고, pH 3.0으로 중성화한 후 에틸 아세테이트(30 mL)로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조하고, 여과한 후 농축하여 조질 화합물 AV(660 mg)를 수득하였다. Step 4: To a solution of compound AU (760 mg, 1.89 mmol) in methanol (4.0 mL) at 55 <0> C was added dropwise sodium hydroxide (98 mg, 2.46 mmol) in water (1 mL). The reaction mixture was stirred at 55 < 0 > C for 2 hours. The reaction mixture was cooled, neutralized to pH 3.0 and extracted three times with ethyl acetate (30 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give crude compound AV (660 mg).
단계 5: 다이클로로메탄(8.0 mL) 중 화합물 AV(776 mg, 2.0 mmol)의 용액에 사이클로프로필 아민(120 mg, 2.0 mmol), HATU(950 mg, 2.5 mmol) 및 다이이소프로필에틸아민(0.5 mL)을 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 빙수를 첨가하여 급랭한 후 다이클로로메탄(30 mL)으로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조한 후 여과하고 농축하여 조질 화합물 AW(578 mg)를 수득하였다. Step 5: To a solution of compound AV (776 mg, 2.0 mmol) in dichloromethane (8.0 mL) was added cyclopropylamine (120 mg, 2.0 mmol), HATU (950 mg, 2.5 mmol) and diisopropylethylamine mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched by the addition of ice water and extracted three times with dichloromethane (30 mL). The combined organic phases were dried over Na 2 SO 4 , filtered and concentrated to give crude Compound AW (578 mg).
단계 6: 다이클로로메탄(1.5 mL) 중 페닐실란(1.5 mL) 및 [Ir(COD)2Cl]2(7 mg, 0.01 mmol)의 혼합물에 화합물 AW(128 mg, 2.0 mmol)를 첨가하였다. 반응 혼합물을 40℃에서 밤새 교반하였다. 반응 혼합물을 농축하고, 이어서 다이클로로메탄(20 mL)으로 희석한 후 다이옥산 용액(3 N) 중 하이드로클로라이드(3 방울)를 첨가하여 급랭하였다. 반응 혼합물을 물로 세척하였다. 유기 상을 분리하고 Na2SO4로 건조한 후 여과하고 농축하였다. 잔사를 컬럼 크로마토그래피로 정제하여 조질 화합물 AX(70 mg)를 수득하였다. Step 6: To a mixture of phenyl silane (1.5 mL) and [Ir (COD) 2 Cl] 2 (7 mg, 0.01 mmol) in dichloromethane (1.5 mL) was added compound AW (128 mg, 2.0 mmol). The reaction mixture was stirred overnight at 40 < 0 > C. The reaction mixture was concentrated and then diluted with dichloromethane (20 mL) and quenched by addition of hydrochloride (3 drops) in dioxane solution (3 N). The reaction mixture was washed with water. The organic phase was separated, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography to give crude Compound AX (70 mg).
단계 7: 다이클로로메탄(2.0 mL) 중 화합물 AX(72 mg, 0.174 mmol)의 용액에 4-니트로페닐 클로로포름에이트(70 mg, 0.35 mmol) 및 다이이소프로필에틸아민(5 방울)을 첨가하였다. 반응 혼합물을 40℃로 2 시간 동안 가열한 후, 이를 농축하고, 잔사를 컬럼 크로마토그래피로 정제하여 화합물 AY(81 mg)를 수득하였다. Step 7: To a solution of compound AX (72 mg, 0.174 mmol) in dichloromethane (2.0 mL) was added 4-nitrophenyl chloroformate (70 mg, 0.35 mmol) and diisopropylethylamine (5 drops). The reaction mixture was heated to 40 < 0 > C for 2 h, then it was concentrated and the residue was purified by column chromatography to give 81 mg of compound AY.
단계 8: 화합물 AY(578 mg, 1.0 mmol) 및 TFA:DCM = 2:1(9 mL)의 혼합물을 실온에서 2 시간 동안 교반하였다. 반응 혼합물을 농축하고, 동시 증발을 위해 톨루엔을 첨가하여 트라이플루오로아세트산을 제거하였다. 잔사를 다이클로로메탄(8.0 mL)에 용해한 후, 다이이소프로필에틸아민(2 mL)을 첨가하였다. 반응 혼합물을 40℃로 3 시간 동안 가열하였다. 반응 혼합물을 농축하여 화합물 AR(239 mg, 조질)을 수득하였다. Step 8: A mixture of compound AY (578 mg, 1.0 mmol) and TFA: DCM = 2: 1 (9 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and toluene was added to remove the trifluoroacetic acid for simultaneous evaporation. The residue was dissolved in dichloromethane (8.0 mL) and diisopropylethylamine (2 mL) was added. The reaction mixture was heated to 40 < 0 > C for 3 h. The reaction mixture was concentrated to give compound AR (239 mg, crude).
실시예 46Example 46
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산2 - [(4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid
실시예 46의 제조Preparation of Example 46
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산(화합물 46-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 46(65 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.42(dd, J = 6.1, 8.7 Hz, 1H), 7.24(dd, J = 2.8, 8.8 Hz, 1H), 7.05(dt, J = 2.5, 8.4 Hz, 1H), 6.17(s, 1H), 4.15-4.02(m, 1H), 3.96-3.71(m, 3H), 3.66-3.53(m, 4H), 3.22-3.07(m, 2H), 2.90(d, J = 11.0 Hz, 1H), 2.80(d, J = 9.0 Hz, 1H), 2.68-2.56(m, 1H), 2.55-2.46(m, 1H), 2.37(dt, J = 3.1, 11.6 Hz, 1H), 2.18(t, J = 10.9 Hz, 1H), 1.03-0.81(m, 4H), MS: 계산치 603(MH+), 측정치 603(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] butanoic acid (compound 46-A). Example 46 (65 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 6.1, 8.7 Hz, 1H ), 7.24 (dd , J = 2.8,8.8 Hz, 1H), 7.05 (dt , J = 2.5,8.4 Hz, 1H), 6.17 (s, 1H), 4.15-4.02 (m, 1H), 3.96-3.71 m, 3H), 3.66-3.53 (m , 4H), 3.22-3.07 (m, 2H), 2.90 (d, J = 11.0 Hz, 1H), 2.80 (d, J = 9.0 Hz, 1H), 2.68-2.56 (m, 1H), 2.55-2.46 (m, 1H), 2.37 (dt , J = 3.1,11.6Hz, 1H), 2.18 (t , J = 10.9Hz, 1H), 1.03-0.81 MS: calcd 603 (MH + ), measurement 603 (MH + ).
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산(화합물 46-A)의 제조Preparation of 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] butanoic acid (Compound 46-
단계 1: 다이클로로메탄(3 mL) 및 Et3N(0.5 mL) 중 t-부틸(3S)-3-포름일-4-메틸-피페라진-1-카복실레이트(화합물 S, 346 mg, 1 mmol)를 4-아미노부탄산(103 mg, 1 mmol)에 첨가하였다. 반응 혼합물을 1 시간 동안 실온에서 교반한 후 감압하에 농축하였다. 이어서, 메탄올(5 mL) 및 나트륨 시아노보로하이드라이드(248 mg, 4 mmol)를 첨가하고, 반응 혼합물을 추가 3 시간 동안 실온에서 교반하였다. 혼합물을 감압하에 농축하여 조질 화합물 46-B를 수득하였다. Step 1: dichloromethane (3 mL) and Et 3 N (0.5 mL) of t- butyl (3S) -3- formaldehyde-4-yl-piperazine-1-carboxylate (Compound S, 346 mg, 1 mmol) was added to 4-aminobutanoic acid (103 mg, 1 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Methanol (5 mL) and sodium cyanoborohydride (248 mg, 4 mmol) were then added and the reaction mixture was stirred for an additional 3 hours at room temperature. The mixture was concentrated under reduced pressure to give crude Compound 46-B.
단계 2: THF(10 mL) 중 화합물 46-B를 칼륨 t-부톡사이드(224 mg, 2 mmol)에 첨가하고, 반응 혼합물을 80℃에서 4 시간 동안 교반하였다. 용액을 실온으로 냉각하고, 수성 HCl 용액으로 pH 5로 산성화하였다. 이어서, 혼합물을 에틸 아세테이트로 3회 추출하였다. 합한 유기 층을 염수로 세척하고, Na2SO4로 건조하고 감압하에 농축하여 조질 화합물 46-C(301 mg)를 수득하였다. Step 2: Compound 46-B in THF (10 mL) was added to potassium t- butoxide (224 mg, 2 mmol) and the reaction mixture was stirred at 80 <0> C for 4 hours. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give crude compound 46-C (301 mg).
단계 3: 화합물 46-C(301 mg, 0.92 mmol)의 교반된 용액을 다이클로로메탄(4 mL)에 용해하고 실온에서 트라이플루오로아세트산(2 mL)으로 처리하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산(화합물 46-A)을 수득하고, 이를 직접 사용하였다. Step 3: A stirred solution of 46-C (301 mg, 0.92 mmol) was dissolved in dichloromethane (4 mL) and treated with trifluoroacetic acid (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give 4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ a] pyrazin-2-yl] butanoic acid (Compound 46-A) was obtained and used directly.
실시예 47Example 47
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산2 - [(4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid
실시예 47의 제조Preparation of Example 47
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-[1-[(8aR)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2일]사이클로프로필]아세트산(화합물 47-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 47(62 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.42(dd, J = 6.1, 8.7 Hz, 1H), 7.24(dd, J = 2.8, 8.8 Hz, 1H), 7.05(dt, J = 2.5, 8.4 Hz, 1H), 6.17(s, 1H), 4.15-4.02(m, 1H), 3.96-3.71(m, 3H), 3.66-3.53(m, 4H), 3.22-3.07(m, 2H), 2.90(d, J = 11.0 Hz, 1H), 2.80(d, J = 9.0 Hz, 1H), 2.68-2.56(m, 1H), 2.55-2.46(m, 1H), 2.37(dt, J = 3.1, 11.6 Hz, 1H), 2.18(t, J = 10.9 Hz, 1H), 1.03-0.81(m, 4H). MS: 계산치 603(MH+), 측정치 603(MH+).(Compound D) instead of 2- [1 - [(8aR) -3-oxo-1,5,6,7-hexahydro-pyrazino [ , 8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] cyclopropyl] acetic acid (Compound 47-A). Example 47 (62 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 6.1, 8.7 Hz, 1H ), 7.24 (dd , J = 2.8,8.8 Hz, 1H), 7.05 (dt , J = 2.5,8.4 Hz, 1H), 6.17 (s, 1H), 4.15-4.02 (m, 1H), 3.96-3.71 m, 3H), 3.66-3.53 (m , 4H), 3.22-3.07 (m, 2H), 2.90 (d, J = 11.0 Hz, 1H), 2.80 (d, J = 9.0 Hz, 1H), 2.68-2.56 (m, 1H), 2.55-2.46 (m, 1H), 2.37 (dt , J = 3.1, 11.6 Hz, 1H), 2.18 (t , J = 10.9 Hz, 1H), 1.03-0.81 (m, 4H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
2-[1-[(8aR)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2일]사이클로프로필]아세트산(화합물 47-A)의 제조2- [1 - [(8aR) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2 yl] cyclopropyl] acetic acid (Compound 47- A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 2-(1-아미노사이클로프로필)아세테이트 하이드로클로라이드 염(이의 합성을 위해 문헌[Sandstroem A., et al., Bioorganic & Medicinal Chemistry, 16(10), 5590-5605; 2008]을 참조한다)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 47-A를 제조하였다.Methyl-2- (1-aminocyclopropyl) acetate hydrochloride salt (for the synthesis of which is described in Sandstroem A., et al., Bioorganic ≪ / RTI > & Medicinal Chemistry, 16 (10), 5590-5605; 2008).
실시예 48Example 48
2-[1-[(8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로프로필]아세트산2- [l- [(8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Acetic acid
실시예 48의 제조Preparation of Example 48
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 2-[1-[(8aR)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2일]사이클로프로필]아세트산(화합물 47-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 48(76 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(s, 1H), 7.76(s, 1H), 7.37-7.23(m, 2H), 7.21-7.10(m, 1H), 6.24(s, 1H), 4.04(d, J = 7.0 Hz, 3H), 3.95-3.77(m, 3H), 3.66-3.54(m, 1H), 3.20-3.08(m, 2H), 2.95-2.86(m, 1H), 2.86-2.74(m, 1H), 2.67-2.57(m, 1H), 2.55-2.45(m, 1H), 2.42-2.30(m, 1H), 2.23-2.12(m, 1H), 1.13(t, J = 7.2 Hz, 3H), 1.01-0.81(m, 4H). MS: 계산치 617(MH+), 측정치 617(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( compound (4R) -6- (bromomethyl) -4- (2-cyanomethyl-phenyl) (Compound C-1) and 2- [1 - [(8aR) -3, 4-dihydro-pyridin- -Acetic acid (Compound 47-A) was used in analogy to Example 1 to yield the title compound as a white solid, MS (ISP): m / e = The title compound was prepared. Example 48 (76 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (s , 1H), 7.76 (s, 1H), 7.37-7.23 (m, 2H), 7.21-7.10 (m, 1H), 6.24 (s, 1H), 4.04 (d , J = 7.0 Hz, 3H), 3.95-3.77 (m, 3H), 3.66-3.54 (m, , 2.86-2.74 (m, 1H), 2.67-2.57 (m, 1H), 2.55-2.45 (m, 1H), 2.42-2.30 (m, 1H), 2.23-2.12 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.01-0.81 (m, 4H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1)의 제조Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (Compound C-1)
메틸 아세토아세테이트 및 2-클로로-4-플루오로벤즈알데하이드 대신에 에틸 아세토아세테이트 및 2-클로로-3-플루오로벤즈알데하이드를 사용하여 화합물 C와 유사하게 화합물 C-1을 제조하였다.Compound C-1 was prepared similarly to compound C using ethylacetoacetate and 2-chloro-3-fluorobenzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluorobenzaldehyde.
실시예 49Example 49
(1S,2R)-2-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid
실시예 49의 제조Preparation of Example 49
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 (1R,2R)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(화합물 49-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 49(48 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.27(s, 2H), 7.21-7.12(m, 1H), 6.24(s, 1H), 4.47-4.38(m, 1H), 4.17-3.98(m, 3H), 3.97-3.86(m, 2H), 3.83-3.75(m, 1H), 3.59(s, 1H), 3.25-3.11(m, 2H), 3.03-2.94(m, 1H), 2.93-2.82(m, 1H), 2.77-2.68(m, 1H), 2.45-2.35(m, 1H), 2.29-2.17(m, 1H), 2.11-1.84(m, 3H), 1.82-1.68(m, 3H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ 2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-1) and (1R, 2R) -2- [ (Compound 49-A), the title compound was obtained as colorless crystals from Example < RTI ID = 0.0 > 1, < / RTI > the title compound was prepared. Example 49 (48 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.27 (s, 2H), 7.21-7.12 (m 2H), 3.83-3.75 (m, 1H), 3.59 (m, 2H), 3.74-3.86 (m, 1H), 2.45-2.35 (m, 1 H), 2.29-2.15 (m, 1H), 2.11-1.84 (m, 3H), 1.82-1.68 (m, 3H), 1.13 (t, J = 7.2 Hz, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
(1R,2R)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(화합물 49-A)의 제조(1R, 2R) -2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2- yl] cyclopentanecarboxylic acid Preparation of compound 49-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 에틸(1R,2R)-2-아미노사이클로펜탄카복실레이트(아셀라 켐바이오 캄파니 리미티드(Accela Chembio Co., Ltd), SY024586)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 49-A를 제조하였다.(1R, 2R) -2-aminocyclopentanecarboxylate (Accela Chembio Co., Ltd.) Instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt, Compound 49-A was prepared similarly to Compound Q of Example 19 using the compound of Example 19 (SY024586).
실시예 50Example 50
(1R,2R)-2-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid
실시예 50의 제조Preparation of Example 50
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 (1S,2R)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(화합물 50-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 50(30 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 6.97-7.39(m, 2H), 6.24(s, 1H), 4.42(d, J = 9.8 Hz, 2H), 3.73-4.19(m, 5H), 3.52(m, 4H), 3.12-3.23(m, 2H), 2.66-2.96(m, 2H), 2.11-2.47(m, 3H), 1.60-2.05(m, 4H), 1.13 ppm(t, J = 7.2 Hz, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ 2-yl-l, 4-dihydropyrimidine-5-carboxylate (Compound C-1) and (lS, 2R) -2- [ (Compound 50-A), the title compound was obtained as colorless crystals from Example < RTI ID = 0.0 > 1, < / RTI > the title compound was prepared. Example 50 (30 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 6.97-7.39 (m, 2H), 6.24 (s (M, 2H), 4.42 (d , J = 9.8 Hz, 2H), 3.73-4.19 (m, 5H), 3.52 (m, 4H), 3.12-3.23 2.11-2.47 (m, 3H), 1.60-2.05 (m, 4H), 1.13 ppm (t , J = 7.2 Hz, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
(1S,2R)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(화합물 50-A)의 제조(1S, 2R) -2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2- yl] cyclopentanecarboxylic acid Preparation of compound 50-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 에틸 (1S,2R)-2-아미노사이클로펜탄카복실레이트 트라이플루오로아세트산 염(화합물 50-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 50-A를 제조하였다.Using ethyl (1S, 2R) -2-aminocyclopentanecarboxylate trifluoroacetic acid salt (Compound 50-B) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt, Compound 50-A was prepared similarly to compound Q of 19.
에틸 (1S,2R)-2-아미노사이클로펜탄카복실레이트 트라이플루오로아세트산 염(화합물 50-B)의 제조Preparation of ethyl (1S, 2R) -2-aminocyclopentanecarboxylate trifluoroacetic acid salt (Compound 50-B)
(1R,2S)-2-(Boc-아미노)사이클로펜탄카복실레이트(CAS: 1140972-29-7, TCI)(1 mmol)를 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후 용매를 진공하에 제거하여 조질 생성물 50-B를 수득하고, 이를 다음 단계에서 직접 사용하였다. (1 R, 2 S) -2- (Boc- amino) cyclopentane carboxylate (CAS: 1140972-29-7, TCI) TFA to (1 mmol) at 0 ℃ was dissolved in CH 2 Cl 2 (3 mL) (1 mL) was slowly added. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give crude product 50-B which was used directly in the next step.
실시예 51Example 51
(1R,2S)-2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실(2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylate
실시예 51의 제조Preparation of Example 51
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 (1R,2S)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 51-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 51(68 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.07-7.89(m, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.44(t, J = 6.9 Hz, 1H), 7.25(dd, J = 2.5, 8.8 Hz, 1H), 7.06(dt, J = 2.5, 8.4 Hz, 1H), 6.18(s, 1H), 4.41(q, J = 8.6 Hz, 1H), 4.19(d, J = 16.8 Hz, 1H), 4.05-3.79(m, 3H), 3.64-3.57(m, 4H), 3.27-3.14(m, 1H), 3.10(dd, J = 4.3, 9.0 Hz, 1H), 2.99(br. s., 1H), 2.94-2.77(m, 2H), 2.48(br. s., 1H), 2.29(br. s., 1H), 2.08-1.84(m, 3H), 1.84-1.69(m, 3H). MS: 계산치 617(MH+), 측정치 617(MH+).(1R, 2S) -2 - [(8aS) -3-oxo-1, 5-dihydro-pyrazino [ The title compound was prepared in analogy to example 1 using 6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (compound 51- . Example 51 (68 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.07-7.89 (m , 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.25 (dd , J = 2.5, 8.8 Hz, 1H), 7.06 (dt, J = 2.5, 8.4 Hz, 1H), 6.18 (s, 1H), 4.41 (q, J = 8.6 Hz, 1H), 4.19 (d, J = J = 4.3, 9.0 Hz, 1 H), 2.99 (br, IH), 3.85-3.57 (m, (s, 1H), 2.94-2.77 (m, 2H), 2.48 (br.s, 1H), 2.29 (br.s, 1H), 2.08-1.84 (m, 3H), 1.84-1.69 , 3H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
(1R,2S)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 51-A)의 제조(1R, 2S) -2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- 2- yl] cyclopentanecarboxylic acid TFA Preparation of salt (Compound 51-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 에틸(1R,2S)-2-아미노사이클로펜탄카복실레이트(아셀라 켐바이오 캄파니 리미티드, CAS: 197916-36-2)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 51-A를 제조하였다.Ethyl (1R, 2S) -2-aminocyclopentanecarboxylate (Acell Chembio Campanilite, CAS: 197916-36-2) was used instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. , Compound 51-A was prepared similarly to Compound Q of Example 19.
실시예 52Example 52
(1S,2S)-2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산(2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Cyclopentanecarboxylic acid
실시예 52의 제조Preparation of Example 52
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 (1S,2S)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 52-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 52(1.7 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 1H NMR(MeOD, 400MHz) d = 7.97(d, J = 3.0 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.42(dd, J = 6.0, 8.8 Hz, 1H), 7.24(dd, J = 2.8, 8.8 Hz, 1H), 7.06(dt, J = 2.8, 8.4 Hz, 1H), 6.18(s, 1H), 4.50-4.25(m, 1H), 4.09(d, J = 17.1 Hz, 1H), 3.98-3.72(m, 3H), 3.61(s, 3H), 3.52(t, J = 8.9 Hz, 1H), 3.26-3.01(m, 2H), 2.96-2.72(m, 3H), 2.41-2.17(m, 2H), 2.05-1.84(m, 3H), 1.81-1.67(m, 3H). MS: 계산치 617(MH+), 측정치 617(MH+).(1S, 2S) -2 - [(8aS) -3-oxo-l, 5-dihydroxy-pyrazino [ The title compound was prepared in analogy to example 1 using 6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (Compound 52- . Example 52 (1.7 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 1 H NMR (MeOD, 400MHz) d = 7.97 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.42 ( (dd , J = 6.0,8.8 Hz, 1H), 7.24 (dd , J = 2.8,8.8 Hz, 1H), 7.06 (dt , J = 2.8,8.4 Hz, 1H), 6.18 (m, 1H), 4.09 ( d, J = 17.1 Hz, 1H), 3.98-3.72 (m, 3H), 3.61 (s, 3H), 3.52 (t, J = 8.9 Hz, 1H), 3.26-3.01 ( m, 2H), 2.96-2.72 (m, 3H), 2.41-2.17 (m, 2H), 2.05-1.84 (m, 3H), 1.81-1.67 (m, 3H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
(1S,2S)-2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 52-A)의 제조(1S, 2S) -2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- 2- yl] cyclopentanecarboxylic acid TFA Preparation of salt (Compound 52-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 에틸 (1S,2S)-2-아미노사이클로펜탄카복실레이트(아셀라 켐바이오 캄파니 리미티드, CAS: 752181-59-2)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 52-A를 제조하였다.Ethyl (1S, 2S) -2-aminocyclopentanecarboxylate (Acellar Chembio Campanilite, CAS: 752181-59-2) was used instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. , Compound 52-A was prepared similarly to Compound Q of Example 19.
실시예 53Example 53
4-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]부탄산Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-
실시예 53의 제조Preparation of Example 53
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산(화합물 46-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 53(2 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.27(s, 2H), 7.16(s, 1H), 6.24(s, 1H), 4.18-4.01(m, 3H), 3.92(d, J = 16.8 Hz, 3H), 3.49(s, 1H), 3.30-3.25(m, 1H), 3.25-3.15(m, 2H), 3.12-3.04(m, 1H), 2.97-2.81(m, 2H), 2.33(s, 3H), 2.26-2.14(m, 1H), 1.85(d, J = 7.0 Hz, 2H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 605(MH+), 측정치 605(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 4 - [(8aS) -3-oxo-thiophene-2- -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] butanoic acid (Compound 46-A) . Example 53 (2 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.27 (s, 2H), 7.16 (s, 1H ), 6.24 (s, 1H), 4.18-4.01 (m, 3H), 3.92 (d , J = 16.8 Hz, 3H), 3.49 m, 2H), 3.12-3.04 (m , 1H), 2.97-2.81 (m, 2H), 2.33 (s, 3H), 2.26-2.14 (m, 1H), 1.85 (d, J = 7.0 Hz, 2H) , 1.13 (t , J = 7.2 Hz, 3 H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
실시예 54Example 54
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid
실시예 54의 제조Preparation of Example 54
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산 TFA 염(화합물 54-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 54(23 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01(d, J = 3.0 Hz, 1H), 7.90(d, J = 3.0 Hz, 1H), 7.53(dd, J = 5.9, 8.7 Hz, 1H), 7.29(dd, J = 2.6, 8.7 Hz, 1H), 7.17-7.06(m, 1H), 6.20(s, 1H), 4.77-4.64(m, 1H), 4.57-4.42(m, 1H), 4.27-4.12(m, 1H), 4.07(dd, J = 3.3, 14.8 Hz, 1H), 3.75-3.62(m, 5H), 3.58(t, J = 9.0 Hz, 1H), 3.51-3.37(m, 2H), 3.27-3.02(m, 4H), 1.95-1.82(m, 1H), 1.80-1.66(m, 1H), 1.31-1.19(m, 6H). MS: 계산치 619(MH+), 측정치 619(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1, using 8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] -2,2- dimethyl-butanoic acid TFA salt (compound 54- Respectively. Example 54 (23 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01 (d , J = 3.0 Hz, 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.53 (dd, J = 5.9, 8.7 Hz, 1H ), 7.29 (dd , J = 2.6,8.7 Hz, 1H), 7.17-7.06 (m, 1H), 6.20 (s, IH), 4.77-4.64 (m, IH), 4.57-4.42 4.27-4.12 (m, 1H), 4.07 (dd, J = 3.3, 14.8 Hz, 1H), 3.75-3.62 (m, 5H), 3.58 (t, J = 9.0 Hz, 1H), 3.51-3.37 (m, 2H), 3.27-3.02 (m, 4H), 1.95-1.82 (m, 1H), 1.80-1.66 (m, 1H), 1.31-1.19 (m, 6H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산 TFA 염(화합물 54-A)의 제조4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] -2,2-dimethyl- Preparation of TFA salt (Compound 54-A)
단계 1: H2O(60 mL) 중 2,2-다이메틸부티로락톤(6.84 g, 60 mmol) 및 KOH(3.36 g)의 혼합물을 2 시간 동안 환류 가열하였다. 용액을 실온으로 냉각하고, 수성 HCl 용액으로 pH 5로 산성화하였다. 이어서, 혼합물을 에틸 아세테이트로 3회 추출하였다. 합한 유기 층을 염수로 세척하고, Na2SO4로 건조하고, 감압하에 농축하여 4-하이드록시-2,2-다이메틸-부탄산 화합물 54-B(4 g)를 수득하였다. Step 1: A mixture of 2,2-dimethylbutyrolactone (6.84 g, 60 mmol) and KOH (3.36 g) in H 2 O (60 mL) was heated to reflux for 2 hours. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted three times with ethyl acetate. To give a butanoic acid compound 54-B (4 g) - The combined organic layers were washed with brine, Na 2 SO 4 dried, and concentrated under reduced pressure to give 4-hydroxy-2,2-dimethyl.
단계 2: 0℃에서 에틸 에터(16 mL) 및 메탄올(24 mL) 중 화합물 54-B(2.2 g, 16.6 mmol)의 혼합물에 트라이메틸실릴다이아조메탄(12.5 mL, 25 mmol)의 헥산 용액(2.0 M)을 첨가하였다. 반응 혼합물을 0℃에서 1 시간 동안 교반하였다. 용매를 증발시키고, 잔사를 에틸 아세테이트 중에 취하고, 희석된 HCl 수용액, 포화 NaHCO3 용액 및 염수로 연속적으로 세척하였다. 혼합물을 Na2SO4로 건조하고, 농축하여 4-하이드록시-2,2-다이메틸-부티르산 메틸 에스터 화합물 54-C(1.5 g)를 수득하였다. Step 2: To a mixture of compound 54-B (2.2 g, 16.6 mmol) in ethyl ether (16 mL) and methanol (24 mL) at 0 C was added a hexane solution of trimethylsilyldiazomethane (12.5 mL, 25 mmol) 2.0 M). The reaction mixture was stirred at 0 < 0 > C for 1 hour. Taken during the solvent was evaporated, and the residue was ethyl acetate and washed successively with a diluted aqueous solution of HCl, saturated NaHCO 3 solution and brine. To afford the butyric acid methyl ester 54-C (1.5 g) - The mixture is dried over Na 2 SO 4, and concentrated to give 4-hydroxy-2,2-dimethyl.
단계 3: 0℃에서 THF(4 mL) 중 알코올 54-C(45 mg, 0.34 mmol)의 용액에 Ph3P(136 mg, 0.52 mmol), 이미다졸(71 mg, 1.04 mmol) 및 I2(132 mg, 0.52 mmol)를 첨가하였다. 1 시간 후, 반응 혼합물을 포화 Na2S2O3 용액으로 급랭하였다. 수층을 헥산으로 2회 추출하였다. 유기 층을 Na2SO4로 건조하고, 진공하에 농축하여 조질 생성물로서 화합물 54-D를 수득하였다. Step 3: To a solution of the alcohol in THF (4 mL) at 0 & The 54-C (45 mg, 0.34 mmol) Ph 3 P (136 mg, 0.52 mmol), imidazole (71 mg, 1.04 mmol) and I 2 (132 mg, 0.52 mmol ) was added to a solution of. After 1 h, the reaction mixture was quenched with saturated Na 2 S 2 O 3 solution. The aqueous layer was extracted twice with hexane. The organic layer was dried with Na 2 SO 4 and concentrated in vacuo to afford the compound 54-D as a crude product.
단계 4: DMF(2 mL) 중 화합물 M(256 mg, 1 mmol)의 교반된 용액에 실온에서 NaH(48 mg, 2 mmol)를 첨가하였다. 반응 혼합물을 20 분 동안 실온에서 교반한 후, 화합물 54-D(256 mg, 1 mmol)를 첨가하였다. 반응 혼합물을 4 시간 동안 실온에서 교반한 후, EA를 첨가하고, 혼합물을 물 및 염수로 세척하였다. 혼합물을 Na2SO4로 건조하고 감압하에 농축하여 조질 생성물을 수득하고, 이를 컬럼으로 정제하여 화합물 54-E(150 mg)를 수득하였다. Step 4: NaH (48 mg, 2 mmol) was added at room temperature to a stirred solution of compound M (256 mg, 1 mmol) in DMF (2 mL). After the reaction mixture was stirred at room temperature for 20 minutes, compound 54-D (256 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, then EA was added and the mixture was washed with water and brine. The mixture was dried over Na 2 SO 4 and concentrated under reduced pressure to give a crude product which was purified by column to give 150 mg of compound 54-E.
단계 5: THF(5 mL) 및 물(2 mL) 중 화합물 54-E(150 mg, 0.4 mmol)의 교반된 용액에 LiOH(96 mg 2.4 mmol)를 첨가하였다. 반응 혼합물을 80℃에서 18 시간 동안 교반한 후, 이를 감압하에 농축하여 조질 생성물을 수득하고, 이를 DCM(4 mL)에 용해하고 TFA(4 mL)로 처리하였다. 혼합물을 2 시간 동안 실온에서 교반한 후 이를 감압하에 농축하여 조질 생성물 54-A를 수득하고, 이를 직접 사용하였다. Step 5: LiOH (96 mg, 2.4 mmol) was added to a stirred solution of compound 54-E (150 mg, 0.4 mmol) in THF (5 mL) and water (2 mL). The reaction mixture was stirred at 80 < 0 > C for 18 h, then it was concentrated under reduced pressure to give a crude product which was dissolved in DCM (4 mL) and treated with TFA (4 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give crude product 54-A which was used directly.
실시예 55Example 55
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-3,3-다이메틸-부탄산4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid
실시예 55의 제조Preparation of Example 55
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3,3-다이메틸-부탄산 TFA 염(화합물 55-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 55(22 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.50-7.35(m, 1H), 7.29-7.20(m, 1H), 7.12-7.01(m, 1H), 6.18(s, 1H), 4.20-4.06(m, 1H), 3.94(s, 3H), 3.61(s, 4H), 3.19(d, J = 14.6 Hz, 3H), 3.08-2.99(m, 1H), 2.97-2.82(m, 2H), 2.47-2.34(m, 1H), 2.27(s, 3H), 1.07(s, 6H). MS: 계산치 619(MH+), 측정치 619(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] -3,3-dimethyl-butanoic acid TFA salt (compound 55- Respectively. Example 55 (22 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.50-7.35 (m, 1H), 7.29-7.20 (s, 3H), 3.61 (s, 4H), 3.19 (d , J) = 14.6 Hz, 3H), 3.08-2.99 (m, 1H), 2.97-2.82 (m, 2H), 2.47-2.34 (m, 1H), 2.27 (s, 3H), 1.07 (s, 6H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
4-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-3,3-다이메틸-부탄산 TFA 염(화합물 55-A)의 제조4 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] -3,3-dimethyl- Preparation of TFA salt (Compound 55-A)
단계 1: 4,4-다이메틸-2-피롤리딘온(2.52 g, 22.3 mmol)을 농축 HCl(50 mL) 및 물(50 mL)의 혼합물에 첨가하고, 생성된 혼합물을 120℃에서 20 시간 동안 환류하였다. 이를 실온으로 냉각한 후, 혼합물을 다이클로로메탄으로 2회 세척하였다. 수층을 증발시켜 백색 고체로서 4-아미노-3,3-다이메틸-부티르산 하이드로클로라이드 화합물 55-B(3.4 g)를 수득하였다. Step 1: 4,4-Dimethyl-2-pyrrolidinone (2.52 g, 22.3 mmol) was added to a mixture of concentrated HCl (50 mL) and water (50 mL) Lt; / RTI > After cooling to room temperature, the mixture was washed twice with dichloromethane. The aqueous layer was evaporated to give 4-amino-3,3-dimethyl-butyric acid hydrochloride compound 55-B (3.4 g) as a white solid.
단계 2: 다이클로로메탄(3 mL) 및 Et3N(0.5 mL) 중 알데하이드 S(346 mg, 1 mmol)를 화합물 55-B(131 mg, 1 mmol)에 첨가하였다. 반응 혼합물을 1 시간 동안 실온에서 교반한 후, 감압하에 농축하였다. 메탄올(5 mL)을 첨가한 후 나트륨 시아노보로하이드라이드(248 mg, 4 mmol)를 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 이를 감압하에 농축하여 조질 생성물 55-C를 수득하였다. Step 2: Aldehyde S (346 mg, 1 mmol) in dichloromethane (3 mL) and Et 3 N (0.5 mL) was added to compound 55-B (131 mg, 1 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Methanol (5 mL) was added followed by sodium cyanoborohydride (248 mg, 4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the crude product 55-C.
단계 3: THF(10 mL) 중 화합물 55-C를 칼륨 t-부톡사이드(224 mg, 2 mmol)에 첨가한 후, 반응 혼합물을 80℃에서 4 시간 동안 교반하였다. 용액을 실온으로 냉각하고, 수성 HCl 용액으로 pH 5로 산성화하였다. 이어서, 혼합물을 에틸 아세테이트로 3회 추출하였다. 합한 유기 층을 염수로 세척하고, Na2SO4로 건조하고 감압하에 농축하여 조질 생성물 55-D를 수득하였다. Step 3: Compound 55-C in THF (10 mL) was added to potassium t-butoxide (224 mg, 2 mmol) and the reaction mixture was stirred at 80 < 0 > C for 4 h. The solution was cooled to room temperature and acidified to pH 5 with aqueous HCl solution. The mixture was then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product 55-D.
단계 4: 다이클로로메탄(4 mL) 중 화합물 55-D(301 mg, 0.92 mmol)의 교반된 용액에 실온에서 트라이플루오로아세트산(2 mL)을 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공하에 제거하여 조질 생성물 55-A를 수득하고, 이를 직접 사용하였다. Step 4: Trifluoroacetic acid (2 mL) was added at room temperature to a stirred solution of compound 55-D (301 mg, 0.92 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give crude product 55-A which was used directly.
실시예 56Example 56
(R)-6-[(S)-2-(2-카복시-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(2-carboxy-ethyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin-7-ylmethyl] -4- (2- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
실시예 56의 제조Preparation of Example 56
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]프로판산 TFA 염(화합물 56-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 56(60 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95-8.00(m, 1H), 7.79(d, 1H), 7.25-7.36(m, 2H), 7.12-7.22(m, 1H), 6.25(s, 1H), 4.24(d, 1H), 4.06(m, 3H), 3.86-4.00(m, 2H), 3.50-3.62(m, 2H), 3.36-3.50(m, 1H), 3.24(m, 1H), 3.15(m, 1H), 3.04(d, 2H), 2.56(m, 3H), 2.40(br. s., 1H), 1.13(m, 3H). MS: 계산치 591(MH+), 측정치 591(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 3 - [(8aS) -3-oxo-thiophene-2- -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] propanoic acid TFA salt (Compound 56-A) Lt; / RTI > Example 56 (60 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95-8.00 (m , 1H), 7.79 (d, 1H), 7.25-7.36 (m, 2H), 7.12-7.22 (m, 1H), 6.25 ( 2H), 3.24 (m, 2H), 3.36-3.50 (m, 1H), 3.24 (m, 1H), 3.15 (m, 1H), 3.04 (d, 2H), 2.56 (m, 3H), 2.40 (br. MS: Calculated 591 (MH < + & gt ; ), found 591 (MH < + & gt ; ).
3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]프로판산 TFA 염(화합물 56-A)의 제조A] pyrazin-2-yl] propanoic acid TFA salt (Compound 56-A) Manufacturing
단계 1: THF(3 mL) 중 화합물 M(150 mg, 0.62 mmol)의 교반된 용액에 실온에서 메틸 아크릴레이트(534 mg, 6.20 mmol)를 첨가한 후 촉매로서 소량의 NaOH를 첨가하였다. LC-MS는 화합물 M이 완전히 소비되었고 생성물 56-B가 이미 형성되었음을 나타낸다. 생성된 혼합물을 실온에서 6 시간 동안 교반하였다. 이어서, 반응 혼합물을 농축하고, 추가 정제 없이 다음 단계에서 직접 사용하였다. 조질 생성물의 양은 180 mg이었다. Step 1: To a stirred solution of compound M (150 mg, 0.62 mmol) in THF (3 mL) at room temperature was added methyl acrylate (534 mg, 6.20 mmol) followed by the addition of a small amount of NaOH as catalyst. LC-MS shows that compound M was completely consumed and product 56-B was already formed. The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated and used directly in the next step without further purification. The amount of the crude product was 180 mg.
단계 2: THF(3 mL) 중 화합물 56-B(180 mg, 0.55 mmol)의 용액에 실온에서 H2O(1 mL) 중 리튬 하이드록사이드 일수화물(116 mg, 2.75 mmol)의 용액을 첨가하였다. 생성된 혼합물을 실온에서 3 시간 동안 교반하였다. LC-MS는 출발 물질 56-B가 완전히 소비되었음을 나타낸다. 혼합물을 1 N HCl로 pH 4 내지 5로 조정한 후 농축하였다. 잔사를 다음 단계에서 직접 사용하였고, 조질 생성물 56-C의 양은 300 mg이었다. Step 2: To a solution of compound 56-B (180 mg, 0.55 mmol) in THF (3 mL) was added a solution of lithium hydroxide monohydrate (116 mg, 2.75 mmol) in H 2 O Respectively. The resulting mixture was stirred at room temperature for 3 hours. LC-MS shows complete consumption of starting material 56-B. The mixture was adjusted to pH 4-5 with 1 N HCI and then concentrated. The residue was used directly in the next step and the amount of crude product 56-C was 300 mg.
단계 3: 다이클로로메탄(3 mL) 중 화합물 56-C(조질, 300 mg, 0.55 mmol)의 용액에 실온에서 트라이플루오로아세트산(3 mL)을 첨가하였다. 생성된 혼합물을 실온에서 2 시간 동안 교반하였다. 반응 혼합물을 농축하고, 잔사를 다음 단계에서 직접 사용하였다. 조질 생성물 56-A의 양은 350 mg이었다. Step 3: To a solution of compound 56-C (crude, 300 mg, 0.55 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was used directly in the next step. The amount of crude product 56-A was 350 mg.
실시예 57Example 57
(R)-6-[(S)-2-((R)-2-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-yl Methyl-4- (2-chloro-3-fluoro-phenyl) -2-thiazol-
실시예 57의 제조Preparation of Example 57
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 (3R)-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산 TFA 염(화합물 57-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 57(48 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.02(d, 1H), 7.91(d, 1H), 7.33-7.41(m, 2H), 7.21 내지 7.29(m, 1H), 6.27(s, 1H), 4.72(d, 1H), 4.54(d, 1H), 4.27-4.38(m, 1H), 4.03-4.19(m, 4H), 3.60-3.74(m, 3H), 3.38-3.48(m, 1H), 3.04-3.25(m, 3H), 2.56-2.66(m, 1H), 2.47-2.56(m, 1H), 1.27(d, 3H), 1.13(m, 3H). MS: 계산치 605(MH+), 측정치 605(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and (3R) -3 - [(8aS) -2-thiazol-2-yl-1,4-dihydropyrimidine- 1-yl) butanoic acid TFA salt (Compound 57-A) was used instead of 3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- , The title compound was prepared. Example 57 (48 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.02 (d , 1H), 7.91 (d, 1H), 7.33-7.41 (m, 2H), 7.21 to 7.29 (m, 1H), 6.27 (s, 4H), 3.60-3.74 (m, 3H), 3.38-3.48 (m, 1H), 4.72 (d, 1H), 1.27 (d, 3H), 1.13 (m, 3H), 3.04-3.25 (m, 3H), 2.56-2.66 (m, MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
(3R)-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산 TFA 염(화합물 57-A)의 제조(3R) -3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] butanoic acid TFA salt 57-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 (3R)-3-아미노부탄오에이트 하이드로클로라이드 염(화합물 57-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 57-A를 제조하였다.(Compound 57-B) was used in place of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt to obtain the compound Q of Example 19 and (2R) -3-aminobutyrate hydrochloride salt Compound 57-A was similarly prepared.
메틸 (3R)-3-아미노부탄오에이트 하이드로클로라이드 염(화합물 57-B)의 제조Preparation of methyl (3R) -3-aminobutaneoate hydrochloride salt (Compound 57-B)
DL-3-아미노이소부티르산 대신에 (R)-3-아미노부탄산을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 57-B를 제조하였다.Compound 57-B was prepared similarly to compound 20 of Example 20 using (R) -3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
실시예 58Example 58
(R)-6-[(S)-2-((S)-2-카복시-1-메틸-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터Methyl-ethyl) -3-oxo-hexahydro-imidazo [1,5-a] pyrazin-7-yl Methyl-4- (2-chloro-3-fluoro-phenyl) -2-thiazol-
실시예 58의 제조Preparation of Example 58
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 (3S)-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산 TFA 염(화합물 58-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 58(50 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01(d, 1H), 7.90(d, 1H), 7.33-7.40(m, 2H), 7.21 내지 7.28(m, 1H), 6.27(s, 1H), 4.66(d, 1H), 4.49(d, 1H), 4.34-4.42(m, 1H), 4.20-4.20(m, 1H), 4.04-4.19(m, 4H), 3.56-3.66(m, 3H), 3.42-3.50(m, 1H), 3.22(m, 1H), 3.01-3.13(m, 2H), 2.50-2.62(m, 2H), 1.23(d, 3H), 1.13(m, 3H). MS: 계산치 605(MH+), 측정치 605(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and (3S) -3 - [(8aS) -2-thiazol- 1-yl) butanoic acid TFA salt (Compound 58-A) was used instead of 3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ , The title compound was prepared. Example 58 (50 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01 (d , 1H), 7.90 (d, 1H), 7.33-7.40 (m, 2H), 7.21 to 7.28 (m, 1H), 6.27 (s, 1H), 4.66 (d, 1H), 4.49 (d, 1H), 4.34-4.42 (m, 2H), 1.23 (d, 3H), 1.13 (m, 3H), 3.42-3.50 (m, . MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
(3S)-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산 TFA 염(화합물 58-A)의 제조(3S) -3 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] butanoic acid TFA salt 58-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 (3S)-3-아미노부탄오에이트 하이드로클로라이드 염(화합물 58-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 58-A를 제조하였다.(Compound 58-B) was used in place of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt to give Compound Q of Example 19 and (2S) -3-aminobutyrate hydrochloride salt Compound 58-A was similarly prepared.
메틸 (3R)-3-아미노부탄오에이트 하이드로클로라이드 염(화합물 58-B)의 제조Preparation of methyl (3R) -3-aminobutaneoate hydrochloride salt (Compound 58-B)
DL-3-아미노이소부티르산 대신에 (S)-3-아미노부탄산을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 58-B를 제조하였다.Compound 58-B was prepared similarly to compound 20 of Example 20 using (S) -3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
실시예 59Example 59
(R)-6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(R) -6 - [(S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- Chloro-4-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-
실시예 59의 제조Preparation of Example 59
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 1-[[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]메틸]사이클로부탄카복실산 TFA 염(화합물 59-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 59(15 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, 1H), 7.76(d, 1H), 7.42(m, 1H), 7.24(m, 1H), 7.06(m, 1H), 6.17(s, 1H), 4.08(d, 1H), 3.90(d, 2H), 3.82-3.86(m, 1H), 3.66-3.72(m, 1H), 3.61(s, 3H), 3.54(d, 1H), 3.47(m, 1H), 3.14-3.23(m, 1H), 3.05(m, 1H), 2.90(d, 1H), 2.80(d, 1H), 2.39-2.47(m, 2H), 2.31-2.39(m, 1H), 2.16(m, 1H), 1.99-2.09(m, 3H), 1.89-1.98(m, 1H). MS: 계산치 617(MH+), 측정치 617(MH+).([(8aS) -3-oxo-l, 5,6,7,8,8-hexahydro-pyrazino [1,2- c] [1,3] oxazin- , 8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] methyl] cyclobutanecarboxylic acid TFA salt (Compound 59-A). Example 59 (15 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 6.17 (m, IH), 3.61 (s, 3H), 3.54 (d, IH) ), 3.47 (m, IH), 3.14-3.23 (m, IH), 3.05 (m, IH), 2.90 2.39 (m, 1H), 2.16 (m, 1H), 1.99-2.09 (m, 3H), 1.89-1. MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
1-[[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]메틸]사이클로부탄카복실산 TFA 염(화합물 59-A)의 제조Yl] methyl] cyclobutanecarboxylic acid TFA salt (compound (1)) was obtained in the same manner as in Synthesis Example 1, except that 1 - [[(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- 59-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 1-아미노메틸-사이클로부탄카복실산 에틸 에스터(이의 합성을 위해 카오(Cao Sheldon X.)(2009) 등의 PCT 국제 출원 WO 2009/067547을 참조한다)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 59-A를 제조하였다.1-Aminomethyl-cyclobutanecarboxylic acid ethyl ester (for its synthesis, PCT international application, such as Cao Sheldon X. (2009), supra), in place of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt WO 2009/067547), compound 59-A was prepared similarly to compound Q of Example 19. < RTI ID = 0.0 >
실시예 60Example 60
6-[(S)-2-(1-카복시-사이클로부틸메틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-((R)-2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터Yl) methyl] -4 - ((R) - (S) -2- (1-carboxy-cyclobutylmethyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Chloro-3-fluoro-phenyl) -2-thiazol-2-yl- l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
실시예 60의 제조Preparation of Example 60
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 1-[[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]메틸]사이클로부탄카복실산 TFA 염(화합물 59-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 59(15 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, 1H), 7.76(d, 1H), 7.23-7.35(m, 2H), 7.16(m, 1H), 6.24(s, 1H), 4.02-4.13(m, 3H), 3.81-3.97(m, 3H), 3.65-3.74(m, 1H), 3.43-3.57(m, 2H), 3.20(m, 1H), 3.05(m, 1H), 2.92(d, 1H), 2.83(d, 1H), 2.31-2.48(m, 3H), 2.17(br. s., 1H), 1.92-2.12(m, 4H), 1.09-1.17(m, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 1 - [[(8aS) -3-fluoro-phenyl) -2-thiazol- Yl] methyl] cyclobutanecarboxylic acid TFA salt (Compound 59-A) was used instead of 2-bromo-5-methylpiperazin-1-ylmethoxy] -1,5,6,7,8,8a-hexahydroimidazo [ , The title compound was prepared. Example 59 (15 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , 1H), 7.76 (d, 1H), 7.23-7.35 (m, 2H), 7.16 (m, 1H), 6.24 (s, 1H) 2H), 3.20 (m, 1H), 3.05 (m, 3H), 3.85-3.77 (m, , 2.92 (d, IH), 2.83 (d, IH), 2.31-2.48 (m, 3H), 2.17 ). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
실시예 61(2개 이성질체의 혼합물)Example 61 (mixture of two isomers)
(R)-6-[(S)-2-((1R,3S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터; 및 (S) -2 - ((1R, 3S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- ] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester; And
(R)-6-[(S)-2-((1S,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(S) -2 - ((1S, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- Yl] -l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester
실시예 61의 제조Preparation of Example 61
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 시스-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 61-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 61(30 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(m, 1H), 7.76(d, 1H), 7.42(m, 1H), 7.24(m, 1H), 7.06(m, 1H), 6.17(s, 1H), 4.24-4.35(m, 1H), 4.10(d, 1H), 3.82-3.94(m, 3H), 3.61(s, 3H), 3.53(m, 1H), 3.03-3.23(m, 2H), 2.77-2.93(m, 3H), 2.36(m, 1H), 2.04-2.23(m, 2H), 1.67-2.00(m, 5H). MS: 계산치 617(MH+), 측정치 617(MH+).Hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one instead of (Compound D) cis - 3 - [(8aS) -3- oxo -1,5,6,7, The title compound was prepared in analogy to example 1 using 8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (compound 61-A). Example 61 (30 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (m , 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 6.17 (s, 3H), 3.53 (m, 1H), 3.03-3.23 (m, 1H), 4.24-4.35 , 2H), 2.77-2.93 (m, 3H), 2.36 (m, 1H), 2.04-2.23 (m, 2H), 1.67-2.00 (m, 5H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
시스Cis -- 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 61-A)의 제조A] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (Compound 61-A, )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 시스-메틸 3-아미노사이클로펜탄카복실레이트 메틸 에스터 하이드로클로라이드 염(화합물 61-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 61-A를 제조하였다.Ethyl 3-amino-2,2-dimethyl-propane-O benzoate hydrochloride salt in place of cis-methyl 3-amino-cyclopentane carboxylate methyl ester hydrochloride salt of the compound of Example 19 using (compound 61-B) Q , ≪ / RTI >
시스Cis -- 메틸 3-아미노사이클로펜탄카복실레이트 메틸 에스터 하이드로클로라이드 염(화합물 61-B)의 제조Preparation of methyl 3-aminocyclopentanecarboxylate methyl ester hydrochloride salt (Compound 61-B)
DL-3-아미노이소부티르산 대신에 시스-3-아미노사이클로펜탄카복실산(아셀라 켐바이오 캄파니 리미티드, CAS: 49805-32-5)을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 61-B를 제조하였다.Compound 61-B was synthesized similarly to Compound 20 of Example 20, using cis-3-aminocyclopentanecarboxylic acid (Acellar Chembio Campanilite, CAS: 49805-32-5) instead of DL-3-aminoisobutyric acid .
실시예 62(2개 이성질체의 혼합물)Example 62 (mixture of two isomers)
(R)-6-[(S)-2-((1R,3S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터; 및 (S) -2 - ((1R, 3S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- ] -4- (2-Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester; And
(R)-6-[(S)-2-((1S,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(S) -2 - ((1S, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- Yl] -l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester <
실시예 62의 제조Preparation of Example 62
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 시스-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 61-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 62(50 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(m, 1H), 7.76(d, 1H), 7.23-7.34(m, 2H), 7.09-7.19(m, 1H), 6.24(s, 1H), 4.23-4.34(m, 1H), 4.01-4.15(m, 3H), 3.83-3.95(m, 3H), 3.53(m, 1H), 3.04-3.23(m, 2H), 2.77-2.95(m, 3H), 2.36(m, 1H), 2.03-2.22(m, 2H), 1.90-2.00(m, 2H), 1.68-1.90(m, 3H), 1.13(m, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ -chloro-3-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylate (compound C-1) and cis-3 - [(8aS) -3 2-yl] cyclopentanecarboxylic acid TFA salt (Compound 61-A) was used as starting material to give the title compound as a white solid. 1H-NMR (DMSO-d6) The title compound was prepared analogously. Example 62 (50 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (m , 1H), 7.76 (d, 1H), 7.23-7.34 (m, 2H), 7.09-7.19 (m, 1H), 6.24 (s, 1H), 4.23-4.34 (m, 1H), 4.01-4.15 (m, 3H), 3.83-3.95 (m, m, 3H), 2.36 (m, 1H), 2.03-2.22 (m, 2H), 1.90-2.00 (m, 2H), 1.68-1.90 (m, 3H), 1.13 (m, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
실시예 63(2개 이성질체의 혼합물)Example 63 (mixture of two isomers)
(R)-6-[(S)-2-((1R,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터; 및 (S) -2 - ((1R, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [l, 5- a] pyrazin- ] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester; And
(R)-6-[(S)-2-((1S,3S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(S) -2 - ((1S, 3S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Yl] -l, 4-dihydro-pyrimidine-5-carboxylic acid methyl ester
실시예 63의 제조Preparation of Example 63
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 트랜스-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 63-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 63(10 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, 1H), 7.76(d, 1H), 7.42(m, 1H), 7.24(m, 1H), 7.06(m, 1H), 6.17(s, 1H), 4.39(d, 1H), 4.10(d, 1H), 3.84-3.92(m, 3H), 3.61(s, 3H), 3.49-3.53(m, 1H), 3.18(d, 1H), 3.06(d, 1H), 2.89(br. s., 3H), 2.38(d, 1H), 2.07-2.19(m, 3H), 1.86-1.97(m, 3H), 1.70(br. s., 1H). MS: 계산치 617(MH+), 측정치 617(MH+).Hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one (Compound D) in place of trans-3 - [(8aS) -3- oxo -1,5,6,7, The title compound was prepared in analogy to example 1 using 8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (compound 63-A). Example 63 (10 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , 1H), 7.76 (d, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 6.17 (s, 3H), 3.49-3.53 (m, IH), 3.18 (d, IH) ), 3.06 (d, 1H), 2.89 (br s, 3H), 2.38 (d, 1H), 2.07-2.19 (m, 3H), 1.86-1.97 (m, 3H), 1.70 (br. , 1H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
트랜스Trance -- 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 63-A)의 제조A] pyrazin-2-yl] cyclopentanecarboxylic acid TFA salt (Compound 63-A )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 트랜스-메틸 3-아미노사이클로펜탄카복실레이트 메틸 에스터 하이드로클로라이드 염(화합물 63-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 63-A를 제조하였다.Methyl-3-aminocyclopentanecarboxylate methyl ester hydrochloride salt (Compound 63-B) was used instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt to obtain Compound Q To give compound 63-A.
트랜스-메틸 3-아미노사이클로펜탄카복실레이트 메틸 에스터 하이드로클로라이드 염(화합물 63-B)의 제조Preparation of trans-methyl 3-aminocyclopentanecarboxylate methyl ester hydrochloride salt (Compound 63-B)
DL-3-아미노이소부티르산 대신에 트랜스-3-아미노사이클로펜탄카복실산(이의 합성을 위해 문헌[Allan, Robin D.; Fong, Joyce Australian Journal of Chemistry (1986), 39(6), 855-64]을 참조한다)을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 63-B를 제조하였다.(Allan, Robin D .; Fong, Joyce Australian Journal of Chemistry (1986), 39 (6), 855-64) for the synthesis of trans - 3-aminocyclopentanecarboxylic acid instead of DL-3-aminoisobutyric acid. , ≪ / RTI > compound 63-B was prepared similarly to compound 20 of Example 20.
실시예 64(2개 이성질체의 혼합물)Example 64 (mixture of two isomers)
(R)-6-[(S)-2-((1R,3R)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터; 및 (S) -2 - ((1R, 3R) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [l, 5- a] pyrazin- ] -4- (2-Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester; And
(R)-6-[(S)-2-((1S,3S)-3-카복시-사이클로펜틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(S) -2 - ((1S, 3S) -3-carboxy-cyclopentyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Yl] -l, 4-dihydro-pyrimidine-5-carboxylic acid ethyl ester <
실시예 64의 제조Preparation of Example 64
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 트랜스-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로펜탄카복실산 TFA 염(화합물 63-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 64(10 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(m, 1H), 7.76(d, 1H), 7.24-7.34(m, 2H), 7.12-7.19(m, 1H), 6.24(s, 1H), 4.34-4.42(m, 1H), 4.02-4.14(m, 3H), 3.83-3.94(m, 3H), 3.51(m, 1H), 3.14-3.22(m, 1H), 3.04-3.10(m, 1H), 2.82-2.94(m, 3H), 2.36(m, 1H), 2.05-2.20(m, 3H), 1.81-1.98(m, 3H), 1.65-1.74(m, 1H), 1.13(m, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ -chloro-3-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylate (compound C-1) and trans-3 - [(8aS) -3 1-yl) cyclopentanecarboxylic acid TFA salt (Compound 63-A) was used instead of 2-chloro- The title compound was prepared analogously. Example 64 (10 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (m , 1H), 7.76 (d, 1H), 7.24-7.34 (m, 2H), 7.12-7.19 (m, 1H), 6.24 (s, 1H), 4.34-4.42 (m, 1H), 4.02-4.14 (m, 3H), 3.83-3.94 (m, 1H), 2.82-2.94 (m, 3H), 2.36 (m, 1H), 2.05-2.20 (m, 3H), 1.81-1.98 m, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
실시예 65Example 65
(R)-6-[2-(4-카복시-벤질)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터Ylmethyl] -4- (2-chloro-4- (4-fluoro-benzyl) -imidazo [1,5- a] pyrazin- Fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5- carboxylic acid methyl ester
실시예 65의 제조Preparation of Example 65
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 4-[(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)메틸]벤조산 TFA 염(화합물 65-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 65(90 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.06(m, 3H), 7.91(m, 1H), 7.53(m, 1H), 7.40 내지 7.45(m, 2H), 7.30(m, 1H), 7.08-7.15(m, 1H), 6.20(d, 1H), 4.75(m, 1H), 4.48-4.62(m, 3H), 4.12-4.25(m, 2H), 3.68-3.78(m, 2H), 3.65(d, 3H), 3.44-3.58(m, 2H), 3.16-3.28(m, 2H), 3.09-3.15(m, 1H). MS: 계산치 639(MH+), 측정치 639(MH+).(3-oxo-1,5,6,7,8,8a-hexahydro-pyrazino [1,2-c] [1,3] oxazin- Yl) methyl] benzoic acid TFA salt (Compound 65-A), the title compound was prepared in analogy to Example 1. Example 65 (90 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.06 (m , 3H), 7.91 (m, 1H), 7.53 (m, 1H), 7.40 to 7.45 (m, 2H), 7.30 (m, 1H), 7.08-7.15 (m, IH), 6.20 (d, IH), 4.75 (m, IH), 4.48-4.62 (m, 3H), 4.12-4.25 2H), 3.65 (d, 3H), 3.44-3.58 (m, 2H), 3.16-3.28 (m, 2H), 3.09-3.15 (m, MS: Calculated 639 (MH < + & gt ; ), Found 639 (MH & lt ; + & gt ; ).
4-[(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)메틸]벤조산 TFA 염(화합물 65-A)의 제조Preparation of 4 - [(3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2- yl) methyl] benzoic acid TFA salt (Compound 65-
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 4-아미노메틸-벤조산 메틸 에스터 하이드로클로라이드를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 65-A를 제조하였다.Compound 65-A was prepared similarly to compound Q of Example 19 using 4-aminomethyl-benzoic acid methyl ester hydrochloride instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
실시예 66Example 66
(R)-6-[2-(4-카복시-벤질)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터Ylmethyl] -4- (2-chloro-3- (4-fluorobenzyl) -3-oxo-hexahydro- Fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydro-pyrimidine-5- carboxylic acid ethyl ester
실시예 66의 제조Preparation of Example 66
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 4-[(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)메틸]벤조산 TFA 염(화합물 65-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 66(82 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.99-8.07(m, 3H), 7.90(m, 1H), 7.40 내지 7.46(m, 2H), 7.32-7.39(m, 2H), 7.21 내지 7.29(m, 1H), 6.26(d, 1H), 4.75(m, 1H), 4.47-4.61(m, 3H), 4.13-4.25(m, 2H), 4.06-4.13(m, 2H), 3.68-3.78(m, 2H), 3.44-3.58(m, 2H), 3.18-3.31(m, 1H), 3.07-3.17(m, 2H), 1.13(m, 3H). MS: 계산치 653(MH+), 측정치 653(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 4 - [(3-oxo-1, 2-dihydro-pyridin- The title compound was prepared in analogy to example 1 using 5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl) methyl] benzoic acid TFA salt (Compound 65- . Example 66 (82 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.99-8.07 (m , 3H), 7.90 (m, 1H), 7.40 to 7.46 (m, 2H), 7.32-7.39 (m, 2H), 7.21 to 2H), 4.06-4.13 (m, 2H), 3.68-7.25 (m, 2H) 3.78 (m, 3H), 3.78 (m, 2H), 3.44-3.58 (m, 2H), 3.18-3.31 (m, MS: Calcd. 653 (MH + ), measurement 653 (MH + ).
실시예 67Example 67
2-[2-[7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]에톡시]아세트산2- [7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] ethoxy] acetic acid
실시예 67의 제조Preparation of Example 67
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 2-[2-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)에톡시]아세트산(화합물 67-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 67(2.5 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-8.01(d, J = 4.0 Hz, 1H), 7.90 내지 7.89(d, J = 4.0 Hz, 1H), 7.35-7.38(m, 2 H), 7.24(m, 1H), 6.26(s, 1H), 4.66(m, 1H), 4.51(m, 1H), 4.05-4.40(m, 5H), 3.70-3.83(m, 3H), 3.52-3.70(m, 3H), 3.40(m, 3H), 3.32(m, 2 H), 1.13(m, 3H). MS: 계산치 621(MH+), 측정치 621(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 2- [2- (3-oxo-pyrrolidine-1-carbonyl) -piperidine- (Compound 67-A), the title compound was prepared analogously to Example 1, but using in the next step the title compound . Example 67 (2.5 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-8.01 (d , J = 4.0 Hz, 1H), 7.90 to 7.89 (d, J = 4.0 Hz , 1H), 7.35-7.38 (m, 2 H ), 7.24 (m, IH), 6.26 (s, IH), 4.66 (m, IH), 4.51 (m, IH), 4.05-4.40 (m, 5H), 3.70-3.83 3.70 (m, 3H), 3.40 (m, 3H), 3.32 (m, 2H), 1.13 (m, 3H). MS: Calculated 621 (MH < + & gt ; ), found 621 (MH < + & gt ; ).
2-[2-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)에톡시]아세트산(화합물 67-A)의 제조A solution of 2- [2- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl) ethoxy] acetic acid (Compound 67- Produce
단계 1: DCM(10 mL) 중 메틸 (±)-4-Boc-피페라진-2-카복실레이트(CAS: 129799-08-2, 2.44 g, 0.01 mol) 및 TEA(1.52 g, 0.015 mol)의 혼합물을 DCM(10 mL) 중 (4-니트로페닐) 카보노클로리데이트(2.42 g, 0.012 mol)의 용액에 첨가하였다. 실온에서 1 시간 후, 유기 층을 물 및 포화 나트륨 바이카보네이트 용액으로 세척하고, 나트륨 설페이트로 건조하였다. 용매를 제거한 후, 조질 생성물 67-B를 수득하고, 정제 없이 다음 단계에서 사용하였다. MS: 계산치 410(MH+), 측정치 410(MH+). Step 1: To a solution of methyl (±) -4-Boc-piperazine-2-carboxylate (CAS: 129799-08-2, 2.44 g, 0.01 mol) and TEA (1.52 g, 0.015 mol) in DCM The mixture was added to a solution of (4-nitrophenyl) carbonyl chloridate (2.42 g, 0.012 mol) in DCM (10 mL). After 1 hour at room temperature, the organic layer was washed with water and saturated sodium bicarbonate solution and dried over sodium sulfate. After removal of the solvent, crude product 67-B was obtained and used in the next step without purification. MS: Calculated 410 (MH + ), found 410 (MH + ).
단계 2: 화합물 67-B(1.0 g, 2.44 mmol), 2-아미노에탄올(1.0 g, 16.4 mmol), TEA(0.49 g, 4.88 mmol) 및 니트로메탄(2 mL)의 혼합물을 130℃에서 마이크로파로 3 시간 동안 가열하였다. 용매를 제거한 후, 잔사를 물로 처리하고, 에틸 아세테이트로 추출하였다. 용매를 제거하여 조질 생성물 67-C를 수득하였다. MS: 계산치 300(MH+), 측정치 300(MH+). Step 2: A mixture of compound 67-B (1.0 g, 2.44 mmol), 2-aminoethanol (1.0 g, 16.4 mmol), TEA (0.49 g, 4.88 mmol) and nitromethane (2 mL) And heated for 3 hours. After removal of the solvent, the residue was treated with water and extracted with ethyl acetate. The solvent was removed to give the crude product 67-C. MS: Calculated 300 (MH + ), found 300 (MH + ).
단계 3: 화합물 67-C(730 mg, 2.44 mmol) 및 BH3ㆍTHF(1M, 4.88 mL)의 혼합물을 24 시간 동안 실온에서 교반한 후, 상기 혼합물을 포화 나트륨 바이카보네이트 수성 용액으로 처리하고, 에틸 아세테이트로 추출하였다. 용매를 제거한 후, 생성물 67-D를 수득하였다. MS: 계산치 286(MH+), 측정치 286(MH+). Step 3: A mixture of compound 67-C (730 mg, 2.44 mmol) and BH 3 .THF (1 M, 4.88 mL) was stirred at room temperature for 24 h, then the mixture was treated with saturated sodium bicarbonate aqueous solution, And extracted with ethyl acetate. After removal of the solvent, the product 67-D was obtained. MS: Calculated 286 (MH < + & gt ; ), found 286 (MH < + & gt ; ).
단계 4: THF(15 mL) 중 화합물 67-D(0.5 g, 1.75 mmol)의 혼합물을 t-BuOK(0.294g, 2.63 mmol)에 첨가하였다. 30 분 동안 교반한 후, t-부틸 브로모아세테이트(0.68 g, 3.5 mmol)를 이에 첨가하였다. 이어서 혼합물을 실온에서 추가 2 시간 동안 교반하고, 물로 급랭하고, 에틸 아세테이트로 추출하였다. 용매를 제거한 후, 조질 생성물 67-E를 수득하고, 다음 단계에서 사용하였다. MS: 계산치 400(MH+), 측정치 400(MH+). Step 4: A mixture of 67-D (0.5 g, 1.75 mmol) in THF (15 mL) was added to t- BuOK (0.294 g, 2.63 mmol). After stirring for 30 minutes t -butyl bromoacetate (0.68 g, 3.5 mmol) was added thereto. The mixture was then stirred at room temperature for an additional 2 hours, quenched with water and extracted with ethyl acetate. After removal of the solvent, crude product 67-E was obtained and used in the next step. MS: Calculated 400 (MH + ), found 400 (MH + ).
단계 5: DCM(5 mL) 중 화합물 67-E(0.70 g, 1.75 mmol)의 혼합물을 TFA(2 mL)로 처리하였다. 1 시간 동안 실온에서 교반한 후, 용매 및 TFA 잔사를 감압하에 제거하여 생성물 67-A를 수득하였다. MS: 계산치 244(MH+), 측정치 244(MH+). Step 5: Treat a mixture of compound 67-E (0.70 g, 1.75 mmol) in DCM (5 mL) with TFA (2 mL). After stirring for 1 hour at room temperature, the solvent and TFA residue were removed under reduced pressure to give the product 67-A. MS: Calcd. 244 (MH < + & gt ; ), found 244 (MH < + & gt ; ).
실시예 68Example 68
2-[3-[7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]프로폭시]아세트산2 - [(4R) -4- (2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] propoxy] acetic acid
실시예 68의 제조Preparation of Example 68
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 2-[3-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)프로폭시]아세트산(화합물 68-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 68(6.5 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.99-7.98(d, J = 4.0 Hz, 1H), 7.81 내지 7.82(d, J = 4.0 Hz, 1H), 7.32(m, 2 H), 7.21(m, 1H), 6.25(s, 1H), 3.90-4.35(m, 6 H), 3.56(m, 3H), 3.10-3.40(m, 4H), 2.60(m, 2H), 1.85(m, 2H), 1.15(m, 3H). MS: 계산치 635(MH+), 측정치 635(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 2- [3- (3-oxo-pyrrolidine-1-carbonyl) -piperidine- 1-yl) propoxy] acetic acid (Compound 68-A), the title compound was prepared analogously to Example 1, . Example 68 (6.5 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.99-7.98 (d , J = 4.0 Hz, 1H), 7.81 to 7.82 (d, J = 4.0 Hz , 1H), 7.32 (m, 2 H), 2H), 1.85 (m, 2H), 7.21 (m, 1H), 6.25 (s, 1H), 3.90-4.35 , ≪ / RTI > 2H), 1.15 (m, 3H). MS: Calculated 635 (MH < + & gt ; ), found 635 (MH < + & gt ; ).
2-[3-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)프로폭시]아세트산(화합물 68-A)의 제조A solution of 2- [3- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2- yl) propoxy] acetic acid (Compound 68- Produce
2-아미노에탄올 대신에 3-아미노프로판-1-올을 사용하여 화합물 67-A와 유사하게 화합물 68-A를 제조하였다.Compound 68-A was prepared similarly to compound 67-A using 3-aminopropane-1-ol instead of 2-aminoethanol.
실시예 69Example 69
메틸 (4R)-4-(2-클로로-4-플루오로-페닐)-6-[[2-(5-하이드록시-4,4-다이메틸-펜틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -4- (2-chloro-4-fluoro-phenyl) -6- [ Methyl-2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate < / RTI >
실시예 69의 제조Preparation of Example 69
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-(5-하이드록시-4,4-다이메틸-펜틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 69-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 69(55 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97-7.98(d, J = 4.0 Hz, 1H), 7.80 내지 7.81(d, J = 4.0 Hz, 1H), 7.45-7.48(m, 1H), 7.27(m, 1H), 7.08(m, 1H), 6.18(s, 1H), 3.80-4.40(m, 4 H), 3.65(s, 3H), 3.55(m, 1H), 3.10-3.30(m, 6 H), 2.50(m, 2H), 1.50(m, 2H), 1.25(m, 2H), 0.89(s, 6H). MS: 계산치 619(MH+), 측정치 619(MH+).(5-hydroxy-4,4-dimethyl-pentyl) -1,5-dihydro-pyrazino [l, , 6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 69-A). Example 69 (55 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97-7.98 (d , J = 4.0 Hz, 1H), 7.80 to 7.81 (d, J = 4.0 Hz , 1H), 7.45-7.48 (m, 1H) , 7.27 (m, IH), 7.08 (m, IH), 6.18 (s, IH), 3.80-4.40 (m, 4H), 3.65 m, 6 H), 2.50 (m, 2H), 1.50 (m, 2H), 1.25 (m, 2H), 0.89 (s, 6H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
2-(5-하이드록시-4,4-다이메틸-펜틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 69-A)의 제조(5-hydroxy-4,4-dimethyl-pentyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- A)
t-부틸 2-(5-하이드록시-4,4-다이메틸-펜틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 69-B)(1 mmol)를 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후 용매를 진공하에 제거하여 조질 생성물 69-A를 수득하고, 이를 다음 단계에서 직접 사용하였다. t- butyl 2- (5-hydroxy-4,4-dimethyl-pentyl) -3-oxo-tetrahydro--5,6,8,8a- -1H- imidazo [1,5-a] pyrazin-7 -Carboxylate (Compound 69-B) (1 mmol) was dissolved in CH 2 Cl 2 (3 mL) and TFA (1 mL) was slowly added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give the crude product 69-A which was used directly in the next step.
t-t- 부틸 2-(5-하이드록시-4,4-다이메틸-펜틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 69-B)의 제조Butyl 2- (5-hydroxy-4,4-dimethyl-pentyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [l, 5- a] pyrazine- (Compound 69-B)
2-아미노에탄올 대신에 5-아미노-2,2-다이메틸-펜탄-1-올을 사용하여 화합물 67-D와 유사하게 화합물 69-B를 제조하였다.Compound 69-B was prepared analogously to compound 67-D using 5-amino-2,2-dimethyl-pentan-l-ol instead of 2-aminoethanol.
실시예 70Example 70
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-하이드록시에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Chloro-3-fluoro-phenyl) -6 - [[2- (2-hydroxyethyl) -Imidazo [1,5-a] pyrazin-7-yl] methyl] -2-thiazol-2-yl-1,4- dihydropyrimidine-
실시예 70의 제조Preparation of Example 70
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 2-(2-하이드록시에틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 70-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 70(45 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01-8.02(d, J = 4.0 Hz, 1H), 7.91 내지 7.92(d, J = 4.0 Hz, 1H), 7.38(m, 2 H), 7.27(m, 1H), 6.27(s, 1H), 4.55-4.78(m, 2 H), 4.10-4.25(m, 4 H), 3.72(m, 5H), 3.45(m, 2H), 3.10-3.35(m, 7 H). MS: 계산치 563(MH+), 측정치 563(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 2- (2-hydroxyethyl) - lH-pyrrolo [2,3-c] 1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 70-A). Example 70 (45 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01-8.02 (d , J = 4.0 Hz, 1H), 7.91 to 7.92 (d, J = 4.0 Hz , 1H), 7.38 (m, 2 H), 2H), 3.10-4.25 (m, 2H), 7.27 (m, 1H) 3.35 (m, 7 H). MS: Calcd. 563 (MH + ), measurement 563 (MH + ).
2-(2-하이드록시에틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 70-A)의 제조Preparation of 2- (2-hydroxyethyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 70-A)
t-부틸 2-(2-하이드록시에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 67-D)(1 mmol)를 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후 용매를 진공에서 제거하여 조질 생성물 70-A를 수득하고, 이를 다음 단계에서 직접 사용하였다. t- butyl 2- (2-hydroxyethyl) -3-oxo-tetrahydro--5,6,8,8a- -1H- imidazo [1,5-a] pyrazine-7-carboxylate (Compound 67-D ) (1 mmol) was dissolved in CH 2 Cl 2 (3 mL) and TFA (1 mL) was slowly added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give crude product 70-A which was used directly in the next step.
실시예 71Example 71
에틸 (4R)-4-(2-클로로-3-플루오로-페닐)-6-[[2-(2-하이드록시에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Chloro-3-fluoro-phenyl) -6 - [[2- (2-hydroxyethyl) -Imidazo [1,5-a] pyrazin-7-yl] methyl] -2-thiazol-2-yl-1,4- dihydropyrimidine-
실시예 71의 제조Preparation of Example 71
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2,2-다이메틸-5-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)펜탄산(화합물 71-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 71(45 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01-8.02(d, J = 4.0 Hz, 1H), 7.91 내지 7.92(d, J = 4.0 Hz, 1H), 7.53(m, 1H), 7.40(m, 1H), 7.10(m, 1H), 6.20(s, 1H), 4.52-4.75(m, 2 H), 4.10-4.25(m, 2 H), 3.65(m, 5H), 3.45(m, 1H), 3.10-3.35(m, 4 H), 1.55(m, 4H), 1.20(s, 6H). MS: 계산치 563(MH+), 측정치 563(MH+).(3-oxo-1,5,6,7) instead of 2,6-dimethyl-hexahydro-pyrazino [l, 2- , 8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl) pentanoic acid (Compound 71-A). Example 71 (45 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01-8.02 (d , J = 4.0 Hz, 1H), 7.91 to 7.92 (d, J = 4.0 Hz , 1H), 7.53 (m, 1H), 7.40 (m, 2H), 3.65 (m, 5H), 3.45 (m, 2H) , 1H), 3.10-3.35 (m, 4H), 1.55 (m, 4H), 1.20 (s, 6H). MS: Calcd. 563 (MH + ), measurement 563 (MH + ).
2,2-다이메틸-5-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)펜탄산(화합물 71-A)의 제조(3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl) pentanoic acid (Compound 71-A )
단계 1: DMF(10 mL) 중 t-부틸 2-(5-하이드록시-4,4-다이메틸-펜틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 69-B)(0.4 g, 1.1 mmol) 및 피리디늄 다이크로메이트(1.7 g, 4.4 mmol)의 혼합물을 12 시간 동안 교반한 후 물로 처리하고, 아세트산으로 pH 7 미만으로 조정하고, 에틸 아세테이트로 추출하였다. 용매를 제거한 후, 조질 생성물 71-B를 수득하였다. MS: 계산치 370(MH+), 측정치 370(MH+). Step 1: To a solution of t- butyl 2- (5-hydroxy-4,4-dimethyl-pentyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ (0.4 g, 1.1 mmol) and pyridinium dichromate (1.7 g, 4.4 mmol) was stirred for 12 h and then treated with water, The pH was adjusted to below pH 7 with acetic acid and extracted with ethyl acetate. After removal of the solvent, crude product 71-B was obtained. MS: Calcd. 370 (MH + ), measurement 370 (MH + ).
단계 2: DCM(2 mL) 중 화합물 71-B(0.41 g, 1.1 mmol) 및 TFA(2 mL)의 혼합물을 1.2 시간 동안 실온에서 교반하였다. 용매 및 TFA를 제거한 후, 조질 생성물 71-A를 수득하고 다음 단계에서 사용하였다. MS: 계산치 270(MH+), 측정치 270(MH+). Step 2: A mixture of 71-B (0.41 g, 1.1 mmol) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 1.2 h. After removal of the solvent and TFA, crude product 71-A was obtained and used in the next step. MS: Calculated 270 (MH + ), found 270 (MH + ).
실시예 72Example 72
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] cyclohexanecarboxylic acid
실시예 72의 제조Preparation of Example 72
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 시스-4-[(2R)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산 TFA 염(화합물 72-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 72(30 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.42(dd, J = 8.8, 6.3 Hz, 1H), 7.24(dd, J = 8.8, 2.5 Hz, 1H), 7.06(td, J = 8.5, 2.6 Hz, 1H), 6.17(s, 1H), 4.10(d, J = 16.8 Hz, 1H), 3.79-3.97(m, 3H), 3.55-3.70(m, 4H), 3.48(t, J = 8.9 Hz, 1H), 3.11-3.26(m, 1H), 3.03(dd, J = 9.3, 4.0 Hz, 1H), 2.71-2.96(m, 3H), 2.04-2.42(m, 5H), 1.77(br. s., 2H), 1.46-1.62 ppm(m, 3H). MS: 계산치 631(MH+), 측정치 631(MH+).Hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one instead of (Compound D) cis - 4 - [(2R) -3- oxo -1,5,6,7, The title compound was prepared in analogy to example 1 using 8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclohexanecarboxylic acid TFA salt (compound 72-A). Example 72 (30 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 8.8, 6.3 Hz, 1H ), 7.24 (dd, J = 8.8, 2.5 Hz, 1H), 7.06 (td, J = 8.5, 2.6 Hz, 1H), 6.17 (s, 1H), 4.10 (d, J = 16.8 Hz, 1H), 3.79 -3.97 (m, 3H), 3.55-3.70 (m, 4H), 3.48 (t, J = 8.9 Hz, 1H), 3.11-3.26 (m, 1H), 3.03 (dd, J = 9.3, 4.0 Hz, 1H ), 2.71-2.96 (m, 3H), 2.04-2.42 (m, 5H), 1.77 (br s, 2H), 1.46-1.62 ppm (m, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
시스Cis -- 4-[(2R)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산 TFA 염(화합물 72-A)의 제조A] pyrazin-2-yl] cyclohexanecarboxylic acid TFA salt (Compound 72-A (2R) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 시스-4-아미노사이클로헥산카복실레이트 하이드로클로라이드(CAS: 61367-16-6, TCI)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 72-A를 제조하였다.Of Example 19 using: (61367-16-6, TCI CAS) 4- amino-cyclohexane carboxylate hydrochloride was prepared from ethyl 3-amino-2,2-dimethyl-propane-O benzoate hydrochloride salt in place of methyl cis Compound 72-A was prepared similarly to compound Q.
실시예 73Example 73
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산4 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] cyclohexanecarboxylic acid
실시예 73의 제조Preparation of Example 73
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 트랜스-4-[(2R)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산 TFA 염(화합물 73-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 73(46 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.42(dd, J = 8.8, 6.3 Hz, 1H), 7.24(dd, J = 8.5, 2.8 Hz, 1H), 7.06(td, J = 8.5, 2.5 Hz, 1H), 6.17(s, 1H), 4.10(d, J = 17.1 Hz, 1H), 3.78-3.97(m, 3H), 3.61(s, 3H), 3.41-3.52(m, 1H), 3.19(d, J = 11.0 Hz, 1H), 3.03(dd, J = 9.5, 4.0 Hz, 1H), 2.75-2.94(m, 2H), 2.36(dd, J = 11.7, 7.9 Hz, 2H), 1.93-2.24(m, 5H), 1.77(br. s., 2H), 1.53 ppm(d, J = 10.0 Hz, 3H). MS: 계산치 631(MH+), 측정치 631(MH+).Hexahydro-pyrazino [1,2-c] [1,3] oxazin-6-one (Compound D) in place of trans - 4 - [(2R) -3- oxo -1,5,6,7, The title compound was prepared in analogy to example 1 using 8,8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] cyclohexanecarboxylic acid TFA salt (compound 73-A). Example 73 (46 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.42 (dd, J = 8.8, 6.3 Hz, 1H ), 7.24 (dd, J = 8.5, 2.8 Hz, 1H), 7.06 (td, J = 8.5, 2.5 Hz, 1H), 6.17 (s, 1H), 4.10 (d, J = 17.1 Hz, 1H), 3.78 1H), 3.19 (d , J = 11.0 Hz, 1H), 3.03 (dd , J = 9.5, 4.0 Hz, 1H), 3.91 (s, 3H) 2.75-2.94 (m, 2H), 2.36 (dd, J = 11.7, 7.9 Hz, 2H), 1.93-2.24 (m, 5H), 1.77 (br. s., 2H), 1.53 ppm (d, J = 10.0 Hz, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
트랜스Trance -- 4-[(2R)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]사이클로헥산카복실산 TFA 염(화합물 73-A)의 제조A] pyrazin-2-yl] cyclohexanecarboxylic acid TFA salt (Compound 73-A (2R) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸-트랜스-4-아미노-사이클로헥산카복실산 메틸 에스터(CAS: 61367-07-5, TCI)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 73-A를 제조하였다.Example 19 using: (61367-07-5, TCI CAS) cyclohexane carboxylic acid methyl ester-3-ethyl-2,2-dimethyl-trans-4-amino-propane-O-methyl-benzoate hydrochloride salt in place of To give Compound 73-A.
실시예 74Example 74
3-[(8aS)-7-[[(4R)-4-(2-클로로페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산3 - [(8aS) -7 - [[(4R) -4- (2-Chlorophenyl) -5-methoxycarbonyl-2-thiazol- -Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] -2,2-dimethyl-
실시예 74의 제조Preparation of Example 74
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 메틸 (4R)-6-(브로모메틸)-4-(2-클로로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-2) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 74(6 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.41(td, J = 7.4, 1.8 Hz, 2H), 7.19-7.33(m, 2H), 6.21(s, 1H), 4.08(d, J = 17.1 Hz, 1H), 3.79-3.96(m, 3H), 3.60(s, 2H), 3.51(t, J = 9.2 Hz, 1H), 3.37-3.42(m, 1H), 3.07-3.28(m, 3H), 2.74-2.94(m, 2H), 2.12-2.41(m, 4H), 1.39(d, J = 6.3 Hz, 2H), 1.18 ppm(d, J = 4.0 Hz, 3H). MS: 계산치 587(MH+), 측정치 587(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propanoate was used instead of compound C) and hexahydro-pyrazino [ 2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-2) and 3 - [(8aS) -3-oxo-1,5,6 , 7,8,8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid (Compound Q) . Example 74 (6 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.41 (td, J = 7.4, 1.8 Hz, 2H ), 7.19-7.33 (m, 2H) , 6.21 (s, 1H), 4.08 (d, J = 17.1 Hz, 1H), 3.79-3.96 (m, 3H), 3.60 (s, 2H), 3.51 (t, J = 9.2 Hz, 1H), 3.37-3.42 (m, 1H), 3.07-3.28 (m, 3H), 2.74-2.94 (m, 2H), 2.12-2.41 (m, 4H), 1.39 (d, J = 6.3 Hz, 2H), 1.18 ppm (d , J = 4.0 Hz, 3H). MS: Calculated 587 (MH < + & gt ; ), found 587 (MH < + & gt ; ).
메틸 (4R)-6-(브로모메틸)-4-(2-클로로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-2)의 제조2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-2) was obtained in the same manner as in (2- Manufacturing
2-클로로-4-플루오로벤즈알데하이드 대신에 2-클로로벤즈알데하이드를 사용하여 화합물 C와 유사하게 화합물 C-2를 제조하였다.Compound C-2 was prepared similarly to compound C using 2-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde.
실시예 75Example 75
2-[[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]부탄산2 - [[(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- -Dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-
실시예 75의 제조Preparation of Example 75
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-[[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]메틸]부탄산 TFA 염(화합물 75-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 75(50 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96-7.97(m, 1H), 7.92(d, J = 3.3 Hz, 1H), 7.54(dd, J = 8.8, 6.0 Hz, 1H), 7.30(dd, J = 8.7, 2.6 Hz, 1H), 7.12(td, J = 8.3, 2.6 Hz, 1H), 6.20(s, 1H), 4.64-4.81(m, 2H), 4.46-4.60(m, 1H), 4.01-4.26(m, 2H), 3.60-3.78(m, 5H), 3.35-3.57(m, 3H), 3.03-3.29(m, 3H), 2.62(dtd, J = 14.1, 8.4, 5.5 Hz, 1H), 1.50-1.74(m, 2H), 0.99 ppm(t, J = 7.4 Hz, 3H). MS: 계산치 605(MH+), 측정치 605(MH+).2 - [[(8aS) -3-oxo-l, 5,6,7,8,8-hexahydro-pyrazino [ , 8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] methyl] butanoic acid TFA salt (Compound 75-A). Example 75 (50 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96-7.97 (m , 1H), 7.92 (d, J = 3.3 Hz, 1H), 7.54 (dd, J = 8.8, 6.0 Hz, 1H), 7.30 (d , J = 8.7,2.6 Hz, 1H), 7.12 (td , J = 8.3,2.6 Hz, 1H), 6.20 (s, 1H), 4.64-4.81 (m, 2H), 4.46-4.60 ), 4.01-4.26 (m, 2H) , 3.60-3.78 (m, 5H), 3.35-3.57 (m, 3H), 3.03-3.29 (m, 3H), 2.62 (dtd, J = 14.1, 8.4, 5.5 Hz , 1H), 1.50-1.74 (m, 2H), 0.99 ppm (t , J = 7.4 Hz, 3H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
2-[[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]메틸]부탄산 TFA 염(화합물 75-A)의 제조A] pyrazin-2-yl] methyl] butanoic acid TFA salt (Compound 75 (a) -A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 2-(아미노메틸)부탄오에이트(이의 합성을 위해 캡테인(Kaptein Bernardus)(2005) 등의 PCT 국제 출원 WO 2005/085462를 참조한다)를 사용하여 화합물 Q와 유사하게 화합물 75-A를 제조하였다.(Amino methyl) butanoate (for its synthesis, Kaptein Bernardus (2005), et al., PCT international application WO < RTI ID = 0.0 > 2005/085462) was used to prepare compound 75-A, analogous to compound Q.
실시예 76Example 76
3-[(8aS)-7-[[(4S)-5-에톡시카본일-4-(3-플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(3-fluoro-2-methyl-phenyl) -2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
실시예 76의 제조Preparation of Example 76
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4S)-6-(브로모메틸)-4-(3-플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-3) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 76(132 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.3 Hz, 1H), 7.75(d, J = 3.3 Hz, 1H), 7.08-7.23(m, 2H), 6.95(t, J = 8.8 Hz, 1H), 5.99(s, 1H), 4.02-4.17(m, 3H), 3.79-4.00(m, 3H), 3.36-3.57(m, 2H), 3.26-3.33(m, 1H), 3.17-3.25(m, 1H), 3.11(dd, J = 9.3, 4.0 Hz, 1H), 2.78-2.99(m, 2H), 2.53(d, J = 2.0 Hz, 3H), 2.39(dd, J = 11.2, 8.2 Hz, 1H), 2.14-2.26(m, 1H), 1.21(d, J = 2.8 Hz, 6H), 1.15 ppm(t, J = 7.2 Hz, 3H). MS: 계산치 599(MH+), 측정치 599(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4S) -6- (bromomethyl) -4- (3-tert-butoxycarbonylamino) propionic acid in place of the compound C) and hexahydro-pyrazino [ (Compound C-3) and 3 - [(8aS) -3-oxo-thiophene-2- -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid (Compound Q) , The title compound was prepared. Example 76 (132 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.3 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.08-7.23 (m, 2H), 6.95 (t 2H), 3.26-3.33 (m, 1H, J = 8.8 Hz, 1H), 5.99 (s, 1H), 4.02-4.17 (m, 3H), 3.79-4.00 ), 3.17-3.25 (m, 1H) , 3.11 (dd, J = 9.3, 4.0 Hz, 1H), 2.78-2.99 (m, 2H), 2.53 (d, J = 2.0 Hz, 3H), 2.39 (dd, J = 11.2, 8.2 Hz, 1H), 2.14-2.26 (m, 1H), 1.21 (d, J = 2.8 Hz, 6H), 1.15 ppm (t, J = 7.2 Hz, 3H). MS: Calcd. 599 (MH + ), Measurement 599 (MH + ).
에틸 (4S)-6-(브로모메틸)-4-(3-플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-3)의 제조(4S) -6- (bromomethyl) -4- (3-fluoro-2-methyl-phenyl) -2-thiazol- (Compound C-3)
2-클로로-4-플루오로벤즈알데하이드 대신에 2-메틸-3-플루오로벤즈알데하이드 및 메틸 아세토아세테이트 대신에 에틸 아세토아세테이트를 사용하여 화합물 C와 유사하게 화합물 C-3을 제조하였다.Compound C-3 was prepared similarly to compound C using 2-methyl-3-fluorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde and ethyl acetoacetate instead of methyl acetoacetate.
실시예 77Example 77
3-[(8aS)-7-[[4-(4-클로로페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산Yl] -1,4-dihydropyrimidin-6-yl] methyl] -1H-pyrazolo [3,4-d] pyrimidin- ] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl-
실시예 77의 제조Preparation of Example 77
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 메틸 6-(브로모메틸)-4-(4-클로로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-4) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)를 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 77(60 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.99(dd, J = 3.1, 1.4 Hz, 1H), 7.80(d, J = 3.3 Hz, 1H), 7.26-7.42(m, 4H), 5.64-5.82(m, 1H), 4.06(dd, J = 16.8, 4.3 Hz, 1H), 3.72-3.90(m, 3H), 3.69(s, 3H), 3.37-3.61(m, 2H), 3.00-3.24(m, 2H), 2.55-2.97(m, 3H), 2.11-2.39(m, 2H), 1.19 ppm(dd, J = 4.4, 2.9 Hz, 6H). MS: 계산치 587(MH+), 측정치 587(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (Bromomethyl) -4- (4-chlorophenyl) -7H-pyrrolo [2,3-d] pyrimidine instead of compound C) and hexahydro- 2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-4) and 3 - [(8aS) -3-oxo-1,5,6,7,8 , 8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid (Compound Q) the title compound was prepared in analogy to example 1. Example 77 (60 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.99 (dd , J = 3.1, 1.4 Hz, 1H), 7.80 (d, J = 3.3 Hz, 1H), 7.26-7.42 (m, 4H), 5.64 -5.82 (m, 1H), 4.06 (dd, J = 16.8, 4.3 Hz, 1H), 3.72-3.90 (m, 3H), 3.69 (s, 3H), 3.37-3.61 (m, 2H), 3.00-3.24 (m, 2H), 2.55-2.97 (m, 3H), 2.11-2.39 (m, 2H), 1.19 ppm (dd, J = 4.4, 2.9 Hz, 6H). MS: Calculated 587 (MH < + & gt ; ), found 587 (MH < + & gt ; ).
메틸 6-(브로모메틸)-4-(4-클로로페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-4)의 제조Preparation of methyl 6- (bromomethyl) -4- (4-chlorophenyl) -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-
반응식 1-1의 다이하이드로피리미딘 중간체의 키랄 SFC 분리 없이, 2-클로로-4-플루오로벤즈알데하이드 대신에 4-클로로벤즈알데하이드를 사용하여 화합물 C와 유사하게 화합물 C-4를 제조하였다.Compound C-4 was prepared analogously to compound C using 4-chlorobenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde, without separation of the chiral SFC of the dihydropyrimidine intermediate of Scheme 1-1.
실시예 78Example 78
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2-메톡시-프로판산3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Propanoic acid
실시예 78의 제조Preparation of Example 78
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 2-메톡시-3-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)프로판산 TFA 염(화합물 78-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 78(25 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01(d, J = 3.3 Hz, 1H), 7.92(d, J = 3.0 Hz, 1H), 7.33-7.43(m, 2H), 7.19-7.30(m, 1H), 6.27(s, 1H), 4.76(d, J = 16.1 Hz, 1H), 4.58(d, J = 16.1 Hz, 1H), 3.96-4.21(m, 6H), 3.41-3.83(m, 10H), 3.10-3.31(m, 5H), 1.13 ppm(t, J = 7.2 Hz, 3H). MS: 계산치 621(MH+), 측정치 621(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 2-methoxy-3- (3-fluoro-phenyl) -2-thiazol- Similar to example 1, using the oxa-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl) propanoic acid TFA salt (Compound 78- The title compound was prepared. Example 78 (25 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01 (d , J = 3.3 Hz, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.33-7.43 (m, 2H), 7.19-7.30 (m, 1H), 6.27 ( s, 1H), 4.76 (d, J = 16.1 Hz, 1H), 4.58 (d, J = 16.1 Hz, 1H), 3.96-4.21 (m, 6H), 3.41-3.83 ( m, 10H), 3.10-3.31 (m, 5H), 1.13 ppm (t , J = 7.2 Hz, 3H). MS: Calculated 621 (MH < + & gt ; ), found 621 (MH < + & gt ; ).
2-메톡시-3-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)프로판산 TFA 염(화합물 78-A)의 제조A solution of 2-methoxy-3- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- )
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 2-(아미노메틸)부탄오에이트(이의 합성을 위해 리앙(Liang, Congxin) 및 펭(Feng, Yangbo)의 US 2007/0072934를 참조한다)를 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 78-A를 제조하였다.(Liang, Congxin and Feng, Yangbo) for the synthesis thereof, in place of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt. 2007/0072934), compound 78-A was prepared similarly to compound Q of Example 19. < RTI ID = 0.0 >
실시예 79Example 79
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]스피로[3.3]헵탄-6-카복실산2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-2-yl] spiro [3.3] heptane- 6-carboxylic acid
실시예 79의 제조Preparation of Example 79
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]스피로[3.3]헵탄-6-카복실산 TFA 염(화합물 79-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 79(7 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.00-7.92(m, 1H), 7.77(d, J = 3.3 Hz, 1H), 7.42(dd, J = 6.3, 8.5 Hz, 1H), 7.24(dd, J = 2.5, 8.8 Hz, 1H), 7.06(dt, J = 2.5, 8.4 Hz, 1H), 6.18(s, 1H), 4.33-4.20(m, 1H), 4.10(dd, J = 4.4, 16.9 Hz, 1H), 3.96-3.73(m, 4H), 3.66-3.58(m, 3H), 3.57-3.46(m, 1H), 3.21-2.97(m, 3H), 2.95-2.80(m, 2H), 2.73(d, J = 10.3 Hz, 1H), 2.44-2.05(m, 8H). MS: 계산치 626(MH+), 측정치 626(MH+).(8aS) -3-oxo-1,5,6,7,8-tetrahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [1,5- a] pyrazin-2-yl] spiro [3.3] heptane-6- carboxylic acid TFA salt (Compound 79- . Example 79 (7 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.00-7.92 (m , 1H), 7.77 (d, J = 3.3 Hz, 1H), 7.42 (dd, J = 6.3, 8.5 Hz, 1H), 7.24 (dd, J = 2.5, 8.8 Hz, 1H), 7.06 (dt, J = 2.5, 8.4 Hz, 1H), 6.18 (s, 1H), 4.33-4.20 (m, 1H), 4.10 (dd, J = 4.4 (M, 2H), 3.96-3.73 (m, 4H), 3.66-3.58 (m, 3H), 3.57-3.46 ), 2.73 (d , J = 10.3 Hz, 1H), 2.44-2.05 (m, 8H). MS: Calculated 626 (MH < + & gt ; ), found 626 (MH < + & gt ; ).
2-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]스피로[3.3]헵탄-6-카복실산 TFA 염(화합물 79-A)의 제조5-a] pyrazin-2-yl] spiro [3.3] heptane-6-carboxylic acid To a solution of 2 - [(8aS) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ Preparation of salt (Compound 79-A)
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 2-아미노스피로[3.3]헵탄-6-카복실레이트 하이드로클로라이드 염(파마블록 (난징) 알앤디 캄파니 리미티드(PharmaBlock (Nanjing) R&D Co. Ltd), PBLG1036)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 79-A를 제조하였다.3.3-heptane-6-carboxylate hydrochloride salt (PharmaBlock (R)) instead of the ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt Compound 79-A was prepared similarly to Compound Q of Example 19, using the compound of Example 19 (Nanjing) R & D Co. Ltd), PBLG1036).
실시예 80Example 80
5-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]펜탄산5 - [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-
실시예 80의 제조Preparation of Example 80
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 5-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]펜탄산 TFA 염(화합물 80-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 80(18 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.02(d, J = 3.0 Hz, 1H), 7.92(d, J = 3.0 Hz, 1H), 7.54(ddd, J = 1.5, 6.0, 8.8 Hz, 1H), 7.30(dd, J = 2.5, 8.5 Hz, 1H), 7.22-7.09(m, 1H), 6.20(s, 1H), 4.76(d, J = 16.1 Hz, 1H), 4.66-4.39(m, 1H), 4.20(td, J = 3.4, 11.7 Hz, 1H), 4.10(td, J = 4.1, 14.8 Hz, 1H), 3.83-3.56(m, 6H), 3.54-3.38(m, 1H), 3.30-3.10(m, 5H), 2.43-2.28(m, 2H), 1.62(dd, J = 3.1, 5.9 Hz, 4H). MS: 계산치 605(MH+), 측정치 605(MH+).(8aS) -3-oxo-1,5,6,7,8-hexahydro-pyrazino [1,2-c] [1,3] oxazin- The title compound was prepared in analogy to example 1 using 8a-hexahydroimidazo [l, 5-a] pyrazin-2-yl] pentanoic acid TFA salt (compound 80-A). Example 80 (18 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.02 (d , J = 3.0 Hz, 1H), 7.92 (d, J = 3.0 Hz, 1H), 7.54 (ddd, J = 1.5, 6.0, 8.8 Hz , 7.30 (dd , J = 2.5, 8.5 Hz, IH), 7.22-7.09 (m, IH), 6.20 (s, IH), 4.76 (d , J = 16.1 Hz, IH), 4.66-4.39 (m, 1H), 4.20 (td , J = 3.4, 11.7 Hz, 1H), 4.10 (td , J = 4.1, 14.8 Hz, 1H), 3.83-3.56 (m, 6H), 3.54-3.38 , 3.30-3.10 (m, 5H), 2.43-2.28 (m, 2H), 1.62 (dd , J = 3.1, 5.9 Hz, 4H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
5-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]펜탄산 TFA 염(화합물 80-A)의 제조A] pyrazin-2-yl] pentanoic acid TFA salt (Compound 80-A) was reacted with 5- Manufacturing
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 5-아미노펜탄오에이트 하이드로클로라이드 염을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 80-A를 제조하였다.Compound 80-A was prepared similarly to compound Q of Example 19 using methyl 5-aminopentanoate hydrochloride salt instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
실시예 81Example 81
3-[[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]메틸]사이클로부탄카복실산Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4 Yl] methyl] cyclobutanecarboxylic acid < / RTI > < RTI ID = 0.0 &
실시예 81의 제조Preparation of Example 81
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 3-[(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)메틸]사이클로부탄카복실산 TFA 염(화합물 81-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 81(7 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.99(d, J = 3.0 Hz, 1H), 7.84(d, J = 2.3 Hz, 1H), 7.43-7.28(m, 2H), 7.27-7.13(m, 1H), 6.25(s, 1H), 4.52-4.33(m, 1H), 4.32-4.18(m, 1H), 4.07(q, J = 7.0 Hz, 3H), 3.68-3.47(m, 2H), 3.32-2.98(m, 7H), 2.65(d, J = 7.5 Hz, 3H), 2.44-2.27(m, 2H), 2.10-1.98(m, 2H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 631(MH+), 측정치 631(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and 3 - [(3-oxo-1, 2-dihydro-pyridin- Yl) methyl] cyclobutanecarboxylic acid TFA salt (Compound 81-A), the title compound was prepared in analogy to Example 1 using Lt; / RTI > Example 81 (7 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.99 (d , J = 3.0 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.43-7.28 (m, 2H), 7.27-7.13 (m, 1H), 6.25 ( s, 1H), 4.52-4.33 (m, 1H), 4.32-4.18 (m, 1H), 4.07 (q, J = 7.0 Hz, 3H), 3.68-3.47 (m, 2H ), 3.32-2.98 (m, 7H) , 2.65 (d, J = 7.5 Hz, 3H), 2.44-2.27 (m, 2H), 2.10-1.98 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H). MS: Calcd. 631 (MH + ), Mass 631 (MH + ).
3-[(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)메틸]사이클로부탄카복실산 TFA 염(화합물 81-A)의 제조Yl) methyl] cyclobutanecarboxylic acid TFA salt (Compound 81-A) was prepared in a manner similar to that described in Example 1, but starting from 3- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ Manufacturing
에틸 3-아미노-2,2-다이메틸-프로판오에이트 하이드로클로라이드 염 대신에 메틸 3-(아미노메틸)사이클로부탄카복실레이트 하이드로클로라이드 염(화합물 81-B)을 사용하여 실시예 19의 화합물 Q와 유사하게 화합물 81-A를 제조하였다. (Compound 81-B) was used instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt to give Compound Q of Example 19 and Similarly, compound 81-A was prepared.
메틸 3-(아미노메틸)사이클로부탄카복실레이트 하이드로클로라이드 염(화합물 81-B)의 제조Preparation of methyl 3- (aminomethyl) cyclobutanecarboxylate hydrochloride salt (Compound 81-B)
DL-3-아미노이소부티르산 대신에 3-(아미노메틸)사이클로부탄카복실산(파마블록 (난징) 알앤디 캄파니 리미티드, CAS: 1310729-95-3)을 사용하여 실시예 20의 화합물 W와 유사하게 화합물 81-B를 제조하였다.Similarly to Compound 20 of Example 20, using compound 3- (aminomethyl) cyclobutanecarboxylic acid (Pharmablock (Nanjing) ALD Co., Ltd., CAS: 1310729-95-3) instead of DL-3-aminoisobutyric acid, compound 81-B.
실시예 82A 및 82B(분리된 2개의 단일 이성질체)Examples 82A and 82B (two isolated isomers)
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-사이클로프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2-cyclopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예Example 82A 및 82B의 제조 82A and 82B
무수 다이메틸포름아미드(3.0 mL) 중 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C, 176 mg, 0.5 mmol)의 교반된 용액에 다이이소프로필에틸아민(1.0 mL), 칼륨 요오다이드(125 mg, 0.75 mmol) 및 화합물 C-1(250 mg, 0.55 mmol)을 첨가하였다. 반응 혼합물을 질소로 플러쉬하고 55℃에서 2 시간 동안 가열하였다. 빙수를 첨가하여 반응 혼합물을 급랭하고, 에틸 아세테이트(30 mL)로 3회 추출하였다. 유기 상을 분리하고, Na2SO4로 건조하고, 여과하고 농축하였다. 잔사를 HPLC로 정제하여 2개 이성질체의 혼합물을 수득하고, 이를 키랄팩 AD-3 컬럼에서 30% 이소프로판올(0.05% DEA)/CO2를 사용하여 SFC에 의해 추가 용해하여 2개의 단일 이성질체를 수득하였다: 82A-1(더 빠른 용리, 77.3 mg, 수율 25%) 및 82B-1(더 느린 용리, 93 mg, 수율 30%). MS: 계산치 617(MH+), 측정치 617(MH+). To a solution of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate in anhydrous dimethylformamide (3.0 mL) Diisopropylethylamine (1.0 mL), potassium iodide (125 mg, 0.75 mmol) and Compound C-1 (250 mg, 0.55 mmol) were added to a stirred solution of sodium hydride (compound 82-C, 176 mg, 0.5 mmol) ). The reaction mixture was flushed with nitrogen and heated at 55 [deg.] C for 2 hours. The reaction mixture was quenched by the addition of ice water and extracted three times with ethyl acetate (30 mL). The organic phase was separated, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by HPLC to give a mixture of the two isomers which were further dissolved by SFC using 30% isopropanol (0.05% DEA) / CO 2 on a Chiralpak AD-3 column to give two single isomers : 82A-1 (faster elution, 77.3 mg, yield 25%) and 82B-1 (slower elution, 93 mg, 30% yield). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
테트라하이드로푸란(0.62 mL) 중 화합물 82A-1(77.3 mg, 0.125 mmol)의 용액을 물(0.62 mL) 중 리튬 하이드록사이드 일수화물(52.7 mg, 1.25 mmol)에 첨가하였다. 반응 혼합물을 35℃에서 2 시간 동안 교반한 후, 이를 1 N 하이드로클로라이드 용액으로 pH 3.0으로 중성화하였다. 혼합물을 에틸 아세테이트(30 mL)로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조하고, 여과한 후 농축하였다. 잔사를 prep-HPLC로 정제하여 실시예 82A(56.2 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.34-7.27(m, 2H), 7.16(s, 1H), 6.25(s, 1H), 4.31(d, J = 17.3 Hz, 1H), 4.10-4.00(m, 2H), 3.91(d, J = 16.8 Hz, 1H), 3.86-3.75(m, 2H), 3.62-3.54(m, 1H), 3.46(dd, J = 5.4, 9.7 Hz, 1H), 3.32-3.28(m, 1H), 3.21-3.08(m, 1H), 2.90(br. s., 1H), 2.55(br. s., 1H), 2.46(t, J = 4.9 Hz, 1H), 1.13(t, J = 7.2 Hz, 3H), 0.77-0.66(m, 4H). MS: 계산치 603(MH+), 측정치 603(MH+).A solution of 82A-1 (77.3 mg, 0.125 mmol) in tetrahydrofuran (0.62 mL) was added to lithium hydroxide monohydrate (52.7 mg, 1.25 mmol) in water (0.62 mL). The reaction mixture was stirred at 35 < 0 > C for 2 hours, then it was neutralized to pH 3.0 with 1 N hydrochloride solution. The mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were dried with Na 2 SO 4 and concentrated after filtration. The residue was purified by prep-HPLC to give Example 82A (56.2 mg). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.34-7.27 (m, 2H), 7.16 (s , 1H), 6.25 (s, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.10-4.00 (m, 2H), 3.91 (d, J = 16.8 Hz, 1H), 3.86-3.75 (m, 2H), 3.62-3.54 (m, 1H), 3.46 (dd , J = 5.4,9.7Hz, 1H), 3.32-3.28 (m, 1H), 3.21-3.08 1H), 2.55 (br.s, 1H), 2.46 (t , J = 4.9 Hz, 1H), 1.13 (t , J = 7.2 Hz, 3H), 0.77-0.66 (m, 4H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
실시예 82B(68.3 mg)를 실시예 82A와 유사하게 제조하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.29(s, 2H), 7.21-7.13(m, 1H), 6.22(s, 1H), 4.24(d, J = 17.1 Hz, 1H), 4.08-3.95(m, 3H), 3.89-3.77(m, 2H), 3.60-3.52(m, 1H), 3.43(dd, J = 5.3, 9.5 Hz, 1H), 3.32-3.28(m, 1H), 3.22-3.12(m, 1H), 3.06(br. s., 1H), 2.66(br. s., 1H), 2.50-2.42(m, 1H), 1.12(t, J = 7.0 Hz, 3H), 0.73(s, 4H). MS: 계산치 603(MH+), 측정치 603(MH+).Example 82B (68.3 mg) was prepared in analogy to example 82A. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.29 (s, 2H), 7.21-7.13 (m 1H), 6.22 (s, IH), 4.24 (d , J = 17.1 Hz, IH), 4.08-3.95 (m, 3H), 3.89-3.77 (m, 2H), 3.60-3.52 (D , J = 5.3, 9.5 Hz, 1H), 3.32-3.28 (m, 1H), 3.22-3.12 (m, 1H), 3.06 ), 2.50-2.42 (m, 1H), 1.12 (t , J = 7.0 Hz, 3H), 0.73 (s, 4H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트 트라이플루오로아세트산 염(화합물 82-C)의 제조Trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate trifluoroacetic acid salt (Compound 82- C)
단계 1: THF(40 mL, 40 mmol) 중 화합물 AV(6.5 g, 16.7 mmol) 및 1.0 M 보란-THF 착체 용액의 혼합물을 32℃에서 밤새 교반하였다. 반응 혼합물을 농축하였다. 잔사를 에틸 아세테이트(60 mL)에 용해하고, 수소 클로라이드 용액(다이옥산 중 4.0 M, 2.0 mL)을 첨가하였다. 혼합물을 에틸 아세테이트(50 mL)로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조하고, 여과하고 농축하였다. 잔사를 컬럼으로 정제하여 화합물 82-C-1(4.0 g)을 수득하였다. Step 1: A mixture of compound AV (6.5 g, 16.7 mmol) and 1.0 M borane-THF complex solution in THF (40 mL, 40 mmol) was stirred overnight at 32 <0> C. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate (60 mL) and a hydrogen chloride solution (4.0 M in dioxane, 2.0 mL) was added. The mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were dried with Na 2 SO 4, filtered and concentrated. The residue was purified by column to obtain Compound 82-C-1 (4.0 g).
단계 2: -78℃에서 질소하에 무수 다이클로로메탄(60 mL) 중 옥살릴 클로라이드(2.0 mL)의 용액에 무수 다이클로로메탄(2.0 mL) 중 다이메틸 설폭사이드(3.3 mL, 47 mmol)를 적가하였다. 첨가 후, 반응 혼합물을 1 시간 동안 -78℃에서 교반하였다. 이어서, 상기 반응 혼합물에 무수 다이클로로메탄(6.0 mL) 중 화합물 82-C-1(4.0 g, 10.7 mmol)을 적가하고, 추가 시간 동안 -78℃에서 교반하였다. 반응 생성물을, 트라이에틸아민(12 mL, 86 mmol)을 30분간에 걸쳐서 적가하여 급랭하였다. 생성된 혼합물을 실온으로 가온하고, 유기 상을 빙수로 세척하고, 분리하고 Na2SO4로 건조한 후 여과하고 농축하여 조질 화합물 82-C-2(3.72 g, 조질)를 수득하고, 이를 직접 사용하였다. Step 2: To a solution of oxalyl chloride (2.0 mL) in anhydrous dichloromethane (60 mL) under nitrogen at-78 C was added dropwise dimethylsulfoxide (3.3 mL, 47 mmol) in anhydrous dichloromethane Respectively. After the addition, the reaction mixture was stirred at -78 < 0 > C for 1 hour. Compound 82-C-1 (4.0 g, 10.7 mmol) in anhydrous dichloromethane (6.0 mL) was then added dropwise to the reaction mixture and stirred for additional time at -78 <0> C. The reaction product was quenched by dropwise addition of triethylamine (12 mL, 86 mmol) over 30 minutes. The resulting mixture was allowed to warm to room temperature, the organic phase was washed with ice water, and separated using dried with Na 2 SO 4, filtered and concentrated to give crude compound 82-C-2 (3.72 g , crude), and direct them Respectively.
단계 3: 다이클로로메탄(10 mL) 중 화합물 82-C-2(930 mg, 2.5 mmol)의 용액에 사이클로프로필아민(260 μL, 3.75 mmol), 촉매량의 아세트산(2 방울) 및 나트륨 트라이아세톡시보로하이드라이드(1.06 g, 5 mmol)를 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응 생성물을 빙수를 첨가하여 급랭하고, 다이클로로메탄(30 mL)으로 2회 추출하고, 유기 상을 나트륨 바이카보네이트 용액으로 세척하고 Na2SO4로 건조한 후 여과하고 농축하여 조질 화합물 82-C-3(1.03 g, 조질)을 수득하였다. Step 3: To a solution of compound 82-C-2 (930 mg, 2.5 mmol) in dichloromethane (10 mL) was added cyclopropylamine (260 L, 3.75 mmol), a catalytic amount of acetic acid (2 drops) and sodium triacetoxy (1.06 g, 5 mmol). The reaction mixture was stirred overnight at room temperature. The reaction product was quenched by adding iced water, extracted twice with dichloromethane (30 mL), the organic phase was washed with sodium bicarbonate solution, dried over Na 2 SO 4 , filtered and concentrated to give crude compound 82-C- 3 (1.03 g, crude).
단계 4: 다이클로로메탄(15 mL) 중 화합물 82-C-3(1.03 g, 2.5 mmol)의 혼합물을 다이이소프로필에틸아민(1.0 mL) 및 4-니트로페닐 클로로포름에이트(1.0 g, 5.0 mmol)에 첨가하였다. 반응 혼합물을 40℃에서 2 시간 동안 교반하였다. 반응 생성물을 빙수를 첨가하여 급랭하고 다이클로로메탄(30 mL)으로 2회 추출하였다. 유기 상을 나트륨 바이카보네이트 용액으로 세척하고 Na2SO4로 건조한 후 여과하고 농축하였다. 잔사를 컬럼으로 정제하여 화합물 82-C-4(1.4 g)를 수득하였다. Step 4: A mixture of compound 82-C-3 (1.03 g, 2.5 mmol) in dichloromethane (15 mL) was treated with diisopropylethylamine (1.0 mL) and 4- nitrophenyl chloroformate (1.0 g, 5.0 mmol) Lt; / RTI > The reaction mixture was stirred at 40 < 0 > C for 2 hours. The reaction product was quenched by addition of ice water and extracted twice with dichloromethane (30 mL). The organic phase was washed with sodium bicarbonate solution and was dried with Na 2 SO 4, filtered and concentrated. The residue was purified by column to obtain Compound 82-C-4 (1.4 g).
단계 5: 화합물 82-C-4(1.4 g, 2.42 mmol) 및 TFA/DCM = 2/1(6 mL)의 혼합물을 실온에서 30 분 동안 교반하였다. 반응 혼합물을 농축하고, 동시 증발을 위해 톨루엔을 첨가하여 트라이플루오로아세트산을 제거하였다. 잔사를 다이클로로메탄(15 mL)에 용해한 후, 다이이소프로필에틸아민(2 mL)을 첨가하였다. 반응 혼합물을 40℃로 밤새 가열하였다. 상기 반응 혼합물에 다이-t-부틸 다이카보네이트(1.1 g, 5.0 mmol)를 첨가하고, 추가 5 시간 동안 교반하였다. 반응 혼합물을 빙수를 첨가하여 급랭하고, 에틸 아세테이트(30 mL)로 2회 추출하였다. 유기 상을 분리하고, Na2SO4로 건조하고, 여과하고 농축하였다. 잔사를 컬럼으로 정제하여 화합물 82-C-5(680 mg)를 수득하였다. Step 5: A mixture of compound 82-C-4 (1.4 g, 2.42 mmol) and TFA / DCM = 2/1 (6 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated and toluene was added to remove the trifluoroacetic acid for simultaneous evaporation. The residue was dissolved in dichloromethane (15 mL) and diisopropylethylamine (2 mL) was added. The reaction mixture was heated to 40 < 0 > C overnight. To the reaction mixture was added di- t- butyl dicarbonate (1.1 g, 5.0 mmol) and stirred for an additional 5 h. The reaction mixture was quenched by the addition of ice water and extracted twice with ethyl acetate (30 mL). The organic phase was separated, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by column to obtain 82-C-5 (680 mg).
단계 6: 화합물 82-C-5(170 mg, 0.5 mmol) 및 TFA/DCM = 2/1(3 mL)의 혼합물을 실온에서 30 분 동안 교반하였다. 반응 혼합물을 농축하고, 동시 증발을 위해 톨루엔을 첨가하여 트라이플루오로아세트산을 제거하여 조질 화합물 82-C를 수득하고, 이를 직접 사용하였다. Step 6: A mixture of compound 82-C-5 (170 mg, 0.5 mmol) and TFA / DCM = 2/1 (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and toluene was added to remove the trifluoroacetic acid for simultaneous evaporation to give crude Compound 82-C which was used directly.
실시예 83A 및 83B(분리된 2개의 단일 이성질체)Examples 83A and 83B (two isolated isomers)
(8R,8aS)-2-사이클로프로필-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -2-Cyclopropyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ; And
(8S,8aR)-2-사이클로프로필-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -2-Cyclopropyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예 83A 및 83B의 제조Preparation of Examples 83A and 83B
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 대신에 메틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-5)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (Compound C-1) instead of methyl (4S) -6- (bromomethyl) -4- (3,4-difluoro-2-methyl- Two title compounds were prepared analogously to Examples 82A and 82B using 4-dihydropyrimidine-5-carboxylate (Compound C-5).
연황색 고체로서 실시예 83A(99 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.14-7.07(m, 1H), 7.06-6.98(m, 1H), 5.93(s, 1H), 4.29(d, J = 17.1 Hz, 1H), 3.88(d, J = 17.3 Hz, 1H), 3.79(br. s., 2H), 3.62(s, 3H), 3.55(s, 1H), 3.46(d, J = 5.5 Hz, 1H), 3.26(d, J = 9.8 Hz, 1H), 3.20-3.09(m, 1H), 2.85(d, J = 10.8 Hz, 1H), 2.56(d, J = 2.3 Hz, 3H), 2.54-2.42(m, 2H), 0.78-0.68(m, 4H). MS: 계산치 587(MH+), 측정치 587(MH+). Example 83A (99 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.14-7.07 (m, 1H), 7.06-6.98 (m, 1H), 5.93 ( s, 1H), 4.29 (d, J = 17.1 Hz, 1H), 3.88 (d, J = 17.3 Hz, 1H), 3.79 (br. s., 2H), 3.62 (s , 3H), 3.55 (s, 1H), 3.46 (d, J = 5.5 Hz, 1H), 3.26 (d, J = 9.8 Hz, 1H), 3.20-3.09 (m, 1H), 2.85 (d, J = 10.8 Hz, 1H), 2.56 (d , J = 2.3 Hz, 3H), 2.54-2.42 (m, 2H), 0.78-0.68 (m, 4H). MS: Calculated 587 (MH < + & gt ; ), found 587 (MH < + & gt ; ).
연황색 고체로서 실시예 83B(72.9 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.94(d, J = 3.3 Hz, 1H), 7.75(d, J = 3.3 Hz, 1H), 7.09(d, J = 4.8 Hz, 2H), 5.90(s, 1H), 4.21(d, J = 17.1 Hz, 1H), 3.97(d, J = 17.1 Hz, 1H), 3.88-3.76(m, 2H), 3.61(s, 3H), 3.58-3.50(m, 1H), 3.46-3.40(m, 1H), 3.28(s, 1H), 3.21-3.12(m, 1H), 3.08-2.99(m, 1H), 2.63(d, J = 3.3 Hz, 1H), 2.56(d, J = 2.3 Hz, 3H), 2.50-2.42(m, 1H), 0.79-0.66(m, 4H). MS: 계산치 587(MH+), 측정치 587(MH+).Example 83B (72.9 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.94 (d , J = 3.3 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.09 (d, J = 4.8 Hz, 2H), 5.90 (s, 1H), 4.21 (d, J = 17.1 Hz, 1H), 3.97 (d, J = 17.1 Hz, 1H), 3.88-3.76 (m, 2H), 3.61 (s, 3H), 3.58-3.50 (m, 1H), 3.46-3.40 ( m, 1H), 3.28 (s, 1H), 3.21-3.12 (m, 1H), 3.08-2.99 (m, 1H), 2.63 (d, J = 3.3 Hz, 1H ), 2.56 (d , J = 2.3 Hz, 3H), 2.50-2.42 (m, 1H), 0.79-0.66 (m, 4H). MS: Calculated 587 (MH < + & gt ; ), found 587 (MH < + & gt ; ).
25% 메탄올(0.05% DEA)/CO2로 용리하는 키랄셀 OJ-H 컬럼에서 화합물 83A-1로부터 실시예 83A를 합성하고(더 빠른 용리) 화합물 83B-1로부터 실시예 83B를 합성하였다(더 느린 용리).Example 83A was synthesized from compound 83A-1 (more rapid elution) in Chiralcel OJ-H column eluting with 25% methanol (0.05% DEA) / CO 2 and compound 83B-1 was synthesized from compound 83B-1 Slow elution).
메틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-5)의 제조Methyl (4S) -6- (bromomethyl) -4- (3,4-difluoro-2-methyl-phenyl) -2-thiazol- - Preparation of carboxylate (Compound C-5)
2-클로로-4-플루오로벤즈알데하이드 대신에 3,4-다이플루오로-2-메틸벤즈알데하이드를 사용하여 화합물 C와 유사하게 화합물 C-5를 제조하였다.Compound C-5 was prepared similarly to compound C using 3,4-difluoro-2-methylbenzaldehyde instead of 2-chloro-4-fluorobenzaldehyde.
실시예 84A 및 84B(분리된 2개의 단일 이성질체)Examples 84A and 84B (two isolated isomers)
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예 84A 및 84B의 제조Preparation of Examples 84A and 84B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-이소프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 84-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- Using 2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazine-8-carboxylate (Compound 84-C) And 2 < RTI ID = 0.0 > 82B. ≪ / RTI >
연황색 고체로서 실시예 84A(20.3 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.11(d, J = 3.0 Hz, 1H), 8.01(d, J = 3.0 Hz, 1H), 7.39(d, J = 2.0 Hz, 2H), 7.28-7.21(m, 1H), 6.32(s, 1H), 4.38(d, J = 17.3 Hz, 1H), 4.08(d, J = 6.5 Hz, 4H), 3.93-3.82(m, 2H), 3.62-3.47(m, 3H), 3.24-3.14(m, 1H), 3.10-3.04(m, 1H), 2.69(d, J = 3.5 Hz, 1H), 1.25-1.11(m, 9H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 84A (20.3 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.11 (d , J = 3.0 Hz, 1H), 8.01 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 2H), 7.28-7.21 (m, 1H), 6.32 (s, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.08 (d, J = 6.5 Hz, 4H), 3.93-3.82 (m, 2H), 3.62 1H), 3.10-3.04 (m, 1H), 2.69 (d , J = 3.5 Hz, 1H), 1.25-1.11 (m, 9H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
연황색 고체로서 실시예 84B(32.5 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.10(s, 1H), 8.02(s, 1H), 7.38(d, J = 4.3 Hz, 2H), 7.29-7.23(m, 1H), 6.30(s, 1H), 4.36(d, J = 16.6 Hz, 1H), 4.14-4.03(m, 4H), 3.87(d, J = 3.3 Hz, 2H), 3.56(d, J = 9.8 Hz, 2H), 3.50-3.44(m, 1H), 3.20(s, 2H), 2.77(d, J = 3.5 Hz, 1H), 1.24-1.10(m, 9H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 84B (32.5 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.10 (s , 1H), 8.02 (s, 1H), 7.38 (d, J = 4.3 Hz, 2H), 7.29-7.23 (m, 1H), 6.30 (s, 1H), 4.36 ( d, J = 16.6 Hz, 1H), 4.14-4.03 (m, 4H), 3.87 (d, J = 3.3 Hz, 2H), 3.56 (d, J = 9.8 Hz, 2H) , 3.50-3.44 (m, 1H), 3.20 (s, 2H), 2.77 (d , J = 3.5 Hz, 1H), 1.24-1.10 (m, 9H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 84A-1로부터 실시예 84A를 합성하고(더 빠른 용리) 화합물 84B-1로부터 실시예 84B를 합성하였다(더 느린 용리).Example 84A was synthesized from Compound 84A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and Compound 84B was synthesized from Compound 84B-1 Slow elution).
메틸 2-이소프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 84-C)의 제조Preparation of methyl 2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 84-C)
사이클로프로필아민 대신에 이소프로필아민을 사용하여 화합물 82-C와 유사하게 화합물 84-C를 제조하였다.Compound 84-C was prepared similarly to compound 82-C using isopropylamine instead of cyclopropylamine.
실시예 85A 및 85B(분리된 2개의 단일 이성질체)Examples 85A and 85B (two isolated single isomers)
(8R,8aS)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4S) -4- (3,4-Difluoro-2-methyl-phenyl) -5-methoxycarbonyl- Yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ; And
(8S,8aR)-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4S) -4- (3,4-Difluoro- Yl] methyl] -2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예 85A 및 85B의 제조Preparation of Examples 85A and 85B
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 대신에 메틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-5)를 사용하고 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-이소프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 84-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (Compound C-1) instead of methyl (4S) -6- (bromomethyl) -4- (3,4-difluoro-2-methyl- 4-dihydro-pyrimidine using 5-carboxylate (compound C-5), and trans-2-methyl-cyclopropyl-3-oxo -1,5,6,7,8,8a- hexahydro-imidazo [1 , 5-a] pyrazine-8-carboxylate (Compound 82-C) instead of methyl 2-isopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ a] pyrazine-8-carboxylate (Compound 84-C), the title compound was prepared in analogy to Examples 82A and 82B.
연황색 고체로서 실시예 85A(3.6 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.10(d, J = 3.3 Hz, 1H), 7.99(d, J = 3.0 Hz, 1H), 7.26-7.19(m, 1H), 7.14-7.04(m, 1H), 6.01(s, 1H), 4.34(d, J = 17.1 Hz, 1H), 4.11(s, 1H), 3.98(d, J = 17.3 Hz, 1H), 3.85(d, J = 4.8 Hz, 2H), 3.65(s, 3H), 3.61-3.54(m, 1H), 3.50(s, 2H), 3.22-3.13(m, 1H), 3.03-2.96(m, 1H), 2.70-2.60(m, 1H), 2.56(d, J = 2.3 Hz, 3H), 1.20(dd, J = 6.8, 14.3 Hz, 6H). MS: 계산치 589(MH+), 측정치 589(MH+).Example 85A (3.6 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.10 (d , J = 3.3 Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.26-7.19 (m, 1H), 7.14-7.04 (m, 1H), 6.01 ( s, 1H), 4.34 (d, J = 17.1 Hz, 1H), 4.11 (s, 1H), 3.98 (d, J = 17.3 Hz, 1H), 3.85 (d, J = 2H), 3.65 (s, 3H), 3.61-3.54 (m, 1H), 3.50 (s, 2H), 3.22-3.13 (m, 1H), 2.56 (d , J = 2.3 Hz, 3H), 1.20 (dd , J = 6.8, 14.3 Hz, 6H). MS: Calculated 589 (MH < + & gt ; ), found 589 (MH < + & gt ; ).
연황색 고체로서 실시예 85B(2.3 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.07(d, J = 3.0 Hz, 1H), 7.96(d, J = 3.3 Hz, 1H), 7.25-7.17(m, 1H), 7.16-7.07(m, 1H), 5.99(s, 1H), 4.30(d, J = 16.8 Hz, 1H), 4.16-3.99(m, 2H), 3.92-3.82(m, 2H), 3.65(s, 3H), 3.59-3.53(m, 1H), 3.51-3.43(m, 2H), 3.24-3.09(m, 2H), 2.78-2.68(m, 1H), 2.55(d, J = 2.3 Hz, 3H), 1.19(dd, J = 6.8, 14.1 Hz, 6H). MS: 계산치 589(MH+), 측정치 589(MH+).Example 85B (2.3 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.07 (d , J = 3.0 Hz, 1H), 7.96 (d, J = 3.3 Hz, 1H), 7.25-7.17 (m, 1H), 7.16-7.07 (m, 1H), 5.99 ( s, 1H), 4.30 (d, J = 16.8 Hz, 1H), 4.16-3.99 (m, 2H), 3.92-3.82 (m, 2H), 3.65 (s, 3H), (M, 2H), 2.78-2.68 (m, 1H), 2.55 (d , J = 2.3 Hz, 3H), 1.19 dd , J = 6.8, 14.1 Hz, 6H). MS: Calculated 589 (MH < + & gt ; ), found 589 (MH < + & gt ; ).
20% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 85A-1로부터 실시예 85A를 합성하고(더 빠른 용리) 화합물 85B-1로부터 실시예 85B를 합성하였다(더 느린 용리).Example 85A was synthesized from compound 85A-1 (faster elution) in Chiralpak AD-3 column eluting with 20% isopropanol (0.05% DEA) / CO 2 and compound 85B-1 was synthesized from compound 85B-1 Slow elution).
실시예 86A 및 86B(분리된 2개의 단일 이성질체)Examples 86A and 86B (two isolated single isomers)
(8R,8aS)-2-t-부틸-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol-2-yl (2S, -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-
실시예 86A 및 86B의 제조Preparation of Examples 86A and 86B
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 대신에 (R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C)를 사용하고 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-t-부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 86-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (compound C-1) instead of (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrido pyrimidine-5-carboxylic acid methyl ester used (compound C) and trans-2-methyl-cyclopropyl-3-oxo -1,5,6,7,8,8a- hexahydro-imidazo [1,5-a] pyrazine 8-carboxylate (compound C-82) instead of 2- methyl-t- butyl-3-oxo -1,5,6,7,8,8a- hexahydro-imidazo [1,5-a] pyrazine to -8 -Carboxylate (Compound 86-C), the title compound was prepared in analogy to example 82A and 82B.
연황색 고체로서 실시예 86A(64.8 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98(d, J = 3.0 Hz, 1H), 7.80(d, J = 3.3 Hz, 1H), 7.52-7.45(m, 1H), 7.24(dd, J = 2.6, 8.7 Hz, 1H), 7.06(d, J = 2.8 Hz, 1H), 6.19(s, 1H), 4.32(d, J = 17.3 Hz, 1H), 3.97(br. s., 1H), 3.82-3.72(m, 2H), 3.65-3.58(m, 4H), 3.57-3.51(m, 1H), 3.42-3.36(m, 1H), 3.19-3.09(m, 1H), 2.99-2.89(m, 1H), 2.65-2.53(m, 1H), 1.41(s, 9H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 86A (64.8 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98 (d , J = 3.0 Hz, 1H), 7.80 (d, J = 3.3 Hz, 1H), 7.52-7.45 (m, 1H), 7.24 (dd ,. J = 2.6, 8.7 Hz , 1H), 7.06 (d, J = 2.8 Hz, 1H), 6.19 (s, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.97 (br. s, 1H ), 3.82-3.72 (m, 2H), 3.65-3.58 (m, 4H), 3.57-3.51 (m, (m, 1 H), 2.65 - 2.53 (m, 1 H), 1.41 (s, 9H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
연황색 고체로서 실시예 86B(71.1 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.46(dd, J = 6.1, 8.7 Hz, 1H), 7.25(dd, J = 2.6, 8.7 Hz, 1H), 7.13-7.05(m, 1H), 6.15(s, 1H), 4.25(d, J = 17.3 Hz, 1H), 4.03(br. s., 1H), 3.86-3.72(m, 2H), 3.65-3.57(m, 4H), 3.55-3.48(m, 1H), 3.41-3.36(m, 1H), 3.19-3.05(m, 2H), 2.75-2.62(m, 1H), 1.40(s, 9H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 86B (71.1 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.46 (dd, J = 6.1, 8.7 Hz, 1H ), 7.25 (dd , J = 2.6, 8.7 Hz, 1H), 7.13-7.05 (m, 1H), 6.15 (s, 1H), 4.25 (d , J = 17.3 Hz, 1H), 4.03 2H), 3.65-3.57 (m, 4H), 3.55-3.48 (m, 1H), 3.41-3.36 -2.62 (m, 1 H), 1.40 (s, 9 H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
25% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 86A-1로부터 실시예 86A를 합성하고(더 빠른 용리) 화합물 86B-1로부터 실시예 86B를 합성하였다(더 느린 용리).Example 86A was synthesized from compound 86A-1 (faster elution) in Chiralpak AD-3 column eluting with 25% isopropanol (0.05% DEA) / CO 2 and 86B- Slow elution).
메틸 2-Methyl 2- t-t- 부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 86-C)의 제조Butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 86-C)
사이클로프로필아민 대신에 t-부틸아민을 사용하여 화합물 82-C와 유사하게 화합물 86-C를 제조하였다.Compound 86-C was prepared similarly to compound 82-C using t- butylamine instead of cyclopropylamine.
실시예 87A 및 87B(분리된 2개의 단일 이성질체)Examples 87A and 87B (two isolated isomers)
(8R,8aS)-2-(8R, 8aS) -2- t-t- 부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및Butyl-7 - [[(4R) -4- (2-chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-2-(8S, 8aR) -2- t-t- 부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산Butyl-7 - [[(4R) -4- (2-chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-
실시예 87A 및 87B의 제조Preparation of Examples 87A and 87B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-t-부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 86-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- Using 2 -t- butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazine-8-carboxylate (Compound 86- Two analogs of the title compound were prepared analogously to 82A and 82B.
화합물 87B-1(단일 이성질체. 구조는 상기 나타낸 2개 중 하나이다): 메틸 (8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실레이트; 또는 메틸 (8R,8aS)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실레이트.Compound 87B-1 (mono-isomer, structure is one of the two indicated above): Methyl (8S, 8aR) -2-t-butyl- - phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-l, 4-dihydropyrimidin-6- yl] methyll-3- oxo-5,6,8,8a-tetrahydro -LH-imidazo [l, 5-a] pyrazine-8-carboxylate; Or methyl (8R, 8aS) -2-t-butyl-7 - [[(4R) -4- (2-chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl-methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine- Late.
연황색 고체로서 화합물 87B-1(316 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.34-7.23(m, 2H), 7.16(t, J = 8.5 Hz, 1H), 6.22(s, 1H), 5.51(s, 2H), 4.14(d, J = 17.1 Hz, 1H), 4.08-4.00(m, 2H), 3.89(s, 1H), 3.81-3.69(m, 5H), 3.58-3.52(m, 1H), 3.35(br. s., 1H), 3.27(d, J = 9.5 Hz, 1H), 3.16-3.04(m, 1H), 2.95(d, J = 12.3 Hz, 1H), 2.52(dt, J = 3.4, 12.0 Hz, 1H), 1.39(s, 9H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 633(MH+), 측정치 633(MH+)Compound 87B-1 (316 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.34-7.23 (m, 2H), 7.16 (t 1H , J = 8.5 Hz, 1H), 6.22 (s, 1H), 5.51 (s, 2H), 4.14 (d , J = 17.1 Hz, 1H), 4.08-4.00 , 3.81-3.69 (m, 5H), 3.58-3.52 (m, IH), 3.35 (br. S., IH), 3.27 (d , J = 9.5 Hz, 2.95 (d , J = 12.3 Hz, 1H), 2.52 (dt , J = 3.4, 12.0 Hz, 1H), 1.39 (s, 9H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calculated 633 (MH +), a measure 633 (MH +)
연황색 고체로서 실시예 87A(52.7 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98(d, J = 3.0 Hz, 1H), 7.79(d, J = 3.0 Hz, 1H), 7.35-7.27(m, 2H), 7.17(s, 1H), 6.25(s, 1H), 4.39-4.28(m, 1H), 4.09-4.01(m, 2H), 3.99-3.86(m, 1H), 3.76(d, J = 9.8 Hz, 2H), 3.64-3.58(m, 1H), 3.57-3.51(m, 1H), 3.40-3.36(m, 1H), 3.13(br. s., 1H), 3.00-2.84(m, 1H), 2.63-2.47(m, 1H), 1.41(s, 9H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 619(MH+), 측정치 619(MH+).Example 87A (52.7 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98 (d , J = 3.0 Hz, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.17 (s , 1H), 6.25 (s, 1H), 4.39-4.28 (m, 1H), 4.09-4.01 (m, 2H), 3.99-3.86 (m, 1H), 3.76 (d, J = 9.8 Hz, 2H), (M, 1H), 3.63-3.58 (m, 1H), 3.57-3.51 (m, 1H), 3.40-3.36 m, 1 H), 1.41 (s, 9 H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
연황색 고체로서 실시예 87B(61.3 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.36-7.26(m, 2H), 7.21-7.14(m, 1H), 6.22(s, 1H), 4.27(d, J = 16.8 Hz, 1H), 4.09-3.97(m, 3H), 3.86-3.71(m, 2H), 3.65-3.55(m, 1H), 3.55-3.46(m, 1H), 3.39-3.34(m, 1H), 3.20-3.02(m, 2H), 2.66(br. s., 1H), 1.40(s, 9H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 619(MH+), 측정치 619(MH+)Example 87B (61.3 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.36-7.26 (m, 2H), 7.21-7.14 (m, 1H), 6.22 (s, 1H), 4.27 (d , J = 16.8 Hz, 1H), 4.09-3.97 (m, 3H), 3.86-3.71 (m, 2H), 3.65-3.55 1H), 1.40 (s, 9H), 1.13 (t , 2H), 3.35-3.46 (m , J = 7.2 Hz, 3 H). MS: Calculated 619 (MH +), a measure 619 (MH +)
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 87A-1로부터 실시예 87A를 합성하고(더 빠른 용리) 화합물 87B-1로부터 실시예 87B를 합성하였다(더 느린 용리).Example 87A was synthesized from compound 87A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and compound 87B-1 was synthesized from compound 87B-1 Slow elution).
실시예 88A 및 88B(분리된 2개의 단일 이성질체)Examples 88A and 88B (two isolated single isomers)
(8R,8aS)-2-t-부틸-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -2-t-Butyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5- methoxycarbonyl- Yl] -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carboxylic acid; And
(8S,8aR)-2-t-부틸-7-[[(4S)-4-(3,4-다이플루오로-2-메틸-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -2-t-Butyl-7 - [[(4S) -4- (3,4- difluoro-2- methyl- phenyl) -5-methoxycarbonyl- Yl] -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Carboxylic acid
실시예 88A 및 88B의 제조Preparation of Examples 88A and 88B
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 대신에 메틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-5)를 사용하고 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-t-부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 86-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (Compound C-1) instead of methyl (4S) -6- (bromomethyl) -4- (3,4-difluoro-2-methyl- 4-dihydro-pyrimidine using 5-carboxylate (compound C-5), and trans-2-methyl-cyclopropyl-3-oxo -1,5,6,7,8,8a- hexahydro-imidazo [1 , 5-a] pyrazine-8-carboxylate (Compound 82-C) in place of methyl 2 -t- butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [ -a] pyrazine-8-carboxylate (Compound 86-C), the title compound was prepared in analogy to Examples 82A and 82B.
연황색 고체로서 실시예 88A(37.2 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.14-7.09(m, 1H), 7.08-6.99(m, 1H), 5.94(s, 1H), 4.32(d, J = 17.1 Hz, 1H), 3.91(d, J = 17.1 Hz, 1H), 3.79-3.71(m, 2H), 3.66-3.58(m, 4H), 3.56-3.50(m, 1H), 3.36(d, J = 9.8 Hz, 1H), 3.17-3.06(m, 1H), 2.89(d, J = 11.3 Hz, 1H), 2.56(d, J = 2.3 Hz, 4H), 1.40(s, 9H). MS: 계산치 603(MH+), 측정치 603(MH+).Example 88A (37.2 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.14-7.09 (m, 1H), 7.08-6.99 (m, 1H), 5.94 (s, 1H), 4.32 (d , J = 17.1 Hz, 1H), 3.91 (d , J = 17.1 Hz, 1H), 3.79-3.71 m, 4H), 3.56-3.50 (m , 1H), 3.36 (d, J = 9.8 Hz, 1H), 3.17-3.06 (m, 1H), 2.89 (d, J = 11.3 Hz, 1H), 2.56 (d , J = 2.3 Hz, 4H), 1.40 (s, 9H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
연황색 고체로서 실시예 88B(61.2 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.3 Hz, 1H), 7.14-7.02(m, 2H), 5.91(s, 1H), 4.25(d, J = 17.1 Hz, 1H), 4.01(d, J = 17.1 Hz, 1H), 3.85-3.72(m, 2H), 3.66-3.56(m, 4H), 3.54-3.46(m, 1H), 3.37(br. s., 1H), 3.20-3.02(m, 2H), 2.69(d, J = 10.3 Hz, 1H), 2.56(d, J = 2.5 Hz, 3H), 1.40(s, 9H). MS: 계산치 603(MH+), 측정치 603(MH+).Example 88B (61.2 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.3 Hz, 1H), 7.14-7.02 (m, 2H), 5.91 (s , 1H), 4.25 (d, J = 17.1 Hz, 1H), 4.01 (d, J = 17.1 Hz, 1H), 3.85-3.72 (m, 2H), 3.66-3.56 (m, 4H), 3.54-3.46 ( (m, 2H), 2.69 (d , J = 10.3 Hz, 1H), 2.56 (d , J = 2.5 Hz, 3H), 1.40 s, 9H). MS: calcd 603 (MH + ), measurement 603 (MH + ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 88A-1로부터 실시예 88A를 합성하고(더 빠른 용리) 화합물 88B-1로부터 실시예 88B를 합성하였다(더 느린 용리).Example 88A was synthesized from compound 88A-1 (more rapid elution) in ChiralPac AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and compound 88B-1 was synthesized from compound 88B-1 Slow elution).
실시예 89Example 89
메틸 7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-2,5,6,8-테트라하이드로-1H-이미다조[1,5-a]피라진-8a-카복실레이트Methyl 7 - [[(4R) -4- (2-chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- -Yl] methyl] -3-oxo-2,5,6,8-tetrahydro-1H-imidazo [1,5- a] pyrazine-8a-
실시예 89의 제조Preparation of Example 89
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 메틸 3-옥소-1,2,5,6,7,8-헥사하이드로이미다조[1,5-a]피라진-8a-카복실레이트 TFA 염(화합물 X)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다.Hexahydro-pyrazino [l, 2-c] [1,3] oxazin-6-one (compound D) in place of methyl 3-oxo-1,2,5,6,7,8-hexahydroimidazo [1,5-a] pyrazine-8a-carboxylate The title compound was prepared in analogy to example 1 using the TFA salt (compound X).
실시예 90A 및 90B(분리된 2개의 단일 이성질체)Examples 90A and 90B (two isolated isomers)
2-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-1,1-다이메틸-3-옥소-6,8-다이하이드로-5H-옥사졸로[3,4-a]피라진-8a-일]아세트산; 및2- [(8aS) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- 6-yl] methyl] -1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo [3,4-a] pyrazin-8-yl] acetic acid; And
2-[(8aR)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-1,1-다이메틸-3-옥소-6,8-다이하이드로-5H-옥사졸로[3,4-a]피라진-8a-일]아세트산2 - [(8aR) -7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl- Yl] methyl] -1,1-dimethyl-3-oxo-6,8-dihydro-5H-oxazolo [3,4- a] pyrazin-
실시예 90A 및 90B의 제조Preparation of Examples 90A and 90B
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 대신에 (R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C)를 사용하고 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-(1,1-다이메틸-3-옥소-5,6,7,8-테트라하이드로옥사졸로[3,4-a]피라진-8a-일)아세테이트(화합물 90-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4- dihydropyrimidine-5-carboxylate (compound C-1) instead of (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrido Methyl-2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine (Compound C) -8-carboxylate (Compound 82-C) instead of methyl 2- (1,1-dimethyl-3-oxo-5,6,7,8-tetrahydrooxazolo [3,4- a] pyrazine-8a -Yl) acetate (Compound 90-C), the title compound was prepared in analogy to Examples 82A and 82B.
연황색 고체로서 실시예 90A(13 mg)를 수득하였다. 1H NMR(400MHz, MeOD) δ ppm 7.92(d, J = 3.3 Hz, 1H), 7.71(d, J = 3.0 Hz, 1H), 7.43(dd, J = 6.0, 8.8 Hz, 1H), 7.23(dd, J = 2.5, 8.8 Hz, 1H), 7.06(dt, J = 2.5, 8.4 Hz, 1H), 6.16(s, 1H), 4.21(d, J = 16.3 Hz, 1H), 3.87-3.71(m, 3H), 3.61(s, 3H), 3.52(d, J = 11.5 Hz, 1H), 3.37(br, 1H), 2.94(d, J = 11.3 Hz, 1H), 2.63(d, J = 16.1 Hz, 1H), 2.46-2.30(m, 2H), 1.47(s, 3H), 1.42(s, 3H). LC/MS: 계산치 592(MH+), 측정치 592(MH+).Example 90A (13 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ ppm 7.92 (d, J = 3.3 Hz, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.43 (dd, J = 6.0, 8.8 Hz, 1H), 7.23 ( dd, J = 2.5, 8.8 Hz , 1H), 7.06 (dt, J = 2.5, 8.4 Hz, 1H), 6.16 (s, 1H), 4.21 (d, J = 16.3 Hz, 1H), 3.87-3.71 (m , 3H), 3.61 (s, 3H), 3.52 (d, J = 11.5 Hz, 1H), 3.37 (br, 1H), 2.94 (d, J = 11.3 Hz, 1H), 2.63 (d, J = 16.1 Hz , 1 H), 2.46-2.30 (m, 2 H), 1.47 (s, 3 H), 1.42 (s, 3 H). LC / MS: calculated 592 (MH + ), found 592 (MH + ).
연황색 고체로서 실시예 90B(25 mg)를 수득하였다. 1H NMR(400MHz, MeOD) δ ppm 7.96(d, J = 3.0 Hz, 1H), 7.75(d, J = 3.0 Hz, 1H), 7.54(dd, J = 6.3, 8.8 Hz, 1H), 7.21(dd, J = 2.8, 8.8 Hz, 1H), 7.06(dt, J = 2.5, 8.4 Hz, 1H), 6.16(s, 1H), 4.09-3.90(m, 2H), 3.89-3.71(m, 2H), 3.66-3.55(m, 4H), 3.36(br, 1H), 2.82(d, J = 8.3 Hz, 1H), 2.72(d, J = 16.8 Hz, 1H), 2.43(d, J = 11.3 Hz, 1H), 2.31(dt, J = 4.0, 11.9 Hz, 1H), 1.57(s, 3H), 1.47(s, 3H); LC/MS: 계산치 592(MH+), 측정치 592(MH+).Example 90B (25 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ ppm 7.96 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.54 (dd, J = 6.3, 8.8 Hz, 1H), 7.21 ( 2H), 3.89-3.71 (m, 2H), 6.96 (d , J = 2.8, 8.8 Hz, 1H), 7.06 (dt , J = 2.5,8.4 Hz, J = 8.3 Hz, 1H), 2.72 (d , J = 16.8 Hz, 1H), 2.43 (d , J = 11.3 Hz, 1H), 3.66-3.55 (m, 4H) 1H), 2.31 (dt , J = 4.0,11.9 Hz, 1H), 1.57 (s, 3H), 1.47 (s, 3H); LC / MS: calculated 592 (MH + ), found 592 (MH + ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 90A-1로부터 실시예 90A를 제조하고(더 빠른 용리) 화합물 90B-1로부터 실시예 90B를 합성하였다(더 느린 용리).Example 90A was prepared (more rapid elution) from compound 90A-1 in chiralpack AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and Example 90B was synthesized from compound 90B-1 Slow elution).
메틸 2-(1,1-다이메틸-3-옥소-5,6,7,8-테트라하이드로옥사졸로[3,4-a]피라진-8a-일)아세테이트(화합물 90-C)의 제조Preparation of methyl 2- (1,1-dimethyl-3-oxo-5,6,7,8-tetrahydrooxazolo [3,4-a] pyrazin-8a- yl) acetate (Compound 90-
단계 1: THF(18 mL) 중 DIPA(3.67 g, 36 mmol, 1.2 당량)의 용액에 -78℃에서 15 분간에 걸쳐서 n-BuLi(2 M, 18 mL, 1.2 당량)를 적가하고, 혼합물을 -78℃에서 추가 15 분 동안 교반하였다. 이어서, THF(30 mL) 중 화합물 AH(10.3 g, 30 mmol, 1.0 당량)를 -78℃에서 반응 생성물에 적가하고, 첨가가 완료된 후, 혼합물을 -78℃에서 추가 30 분 동안 교반하였다. THF(20 mL) 중 BOMCl(7 g, 45 mmol)을 -78℃에서 20 분간에 걸쳐서 적가하고, 반응 생성물을 16 시간 동안 교반하고, 이 기간 동안 온도를 실온으로 가온하였다. 반응 생성물을 1 M HCl(50 mL)로 급랭하고, EA(100 mL)로 2회 추출하고, 유기 층을 건조하고 농축하고, 잔사를 실리카 겔(EA/PE: 0% 내지 20%)로 정제하여 무색 오일로서 화합물 90-C-1(8.2 g)을 수득하였다. Step 1: To a solution of DIPA (3.67 g, 36 mmol, 1.2 eq.) In THF (18 mL) was added dropwise n-BuLi (2 M, 18 mL, 1.2 eq.) Over 15 min at -78 <0>Lt; RTI ID = 0.0 > -78 C < / RTI > Compound AH (10.3 g, 30 mmol, 1.0 eq.) In THF (30 mL) was then added dropwise to the reaction product at -78 째 C and after the addition was complete, the mixture was stirred at -78 째 C for a further 30 minutes. BOMCl (7 g, 45 mmol) in THF (20 mL) was added dropwise over 20 min at -78 <0> C and the reaction product was stirred for 16 h during which time the temperature was allowed to warm to room temperature. The reaction product was quenched with 1 M HCl (50 mL), extracted twice with EA (100 mL), the organic layer was dried and concentrated and the residue was purified with silica gel (EA / PE: 0% to 20% To give compound 90-C-1 (8.2 g) as a colorless oil.
단계 2: MeOH(100 mL) 중 화합물 90-C-1(8.2 g, 17.6 mmol) 및 Pd(OH)2/C(500 mg, 20%)의 혼합물을 실온에서 2 시간 동안 수소하에 교반한 후, 고체를 여과 제거하고, 여액을 농축하고, 잔사를 실리카 겔(EA/PE: 0% 내지 40%)로 정제하여 무색 오일로서 화합물 90-C-2(6.1 g)를 수득하였다. Step 2: A mixture of compound 90-C-1 (8.2 g, 17.6 mmol) and Pd (OH) 2 / C (500 mg, 20%) in MeOH (100 mL) was stirred under hydrogen at room temperature for 2 hours , The solid was filtered off and the filtrate was concentrated and the residue was purified by silica gel (EA / PE: 0% to 40%) to give compound 90-C-2 (6.1 g) as a colorless oil.
단계 3: DMF(20 mL) 중 화합물 90-C-2(3.74 g, 0.01 mol, 1.0 당량) 및 이미다졸(0.81 g, 0.012 mol, 1.2 당량)의 용액에 실온에서 TBSCl(1.65 g, 0.11 mol, 1.1 당량)을 천천히 첨가한 후 혼합물을 실온에서 16 시간 동안 교반하고, EA(50 mL)로 희석하고, 물(50 mL) 및 염수(50 mL)로 세척하고, 유기 층을 Na2SO4로 건조하고, 농축하여 무색 오일로서 화합물 90-C-3(4.4 g)을 수득하였다. MS: 계산치 489(MH+), 측정치 489(MH+). Step 3: To a solution of compound 90-C-2 (3.74 g, 0.01 mol, 1.0 eq.) And imidazole (0.81 g, 0.012 mol, 1.2 eq.) In DMF (20 mL) at room temperature was added TBSCl (1.65 g, 0.11 mol a, 1.1 eq) of the mixture at room temperature was slowly added and stirred for 16 hours, diluted with EA (50 mL), washed with water (50 mL) and brine (50 mL), organic layer was Na 2 SO 4 , And concentrated to give compound 90-C-3 (4.4 g) as a colorless oil. MS: Calcd. 489 (MH + ), Measurement 489 (MH + ).
단계 4: THF(50 mL) 중 화합물 90-C-3(4.4 g, 9 mmol, 1.0 당량)의 용액에 -40℃에서 15 분간에 걸쳐서 CH3MgBr(3.2 M, 15 mL, 5.0 당량)을 적가한 후, 반응 혼합물을 16 시간 동안 교반하고, 상기 온도를 이 기간 동안 실온으로 가온하였다. 반응 생성물을 1 M HCl(50 mL)로 급랭하고, EA(100 mL)로 추출하고, 유기 층을 건조하고 농축하고, 잔사를 실리카 겔(EA/PE: 20% 내지 40%)로 정제하여 무색 오일로서 화합물 90-C-4(1.9 g)를 수득하였다. MS: 계산치 415(MH+), 측정치 415(MH+). Step 4: CH 3 MgBr (3.2 M , 15 mL, 5.0 eq.) Over a period of 15 minutes at -40 ℃ To a solution of THF (50 mL) of compound 90-C-3 (4.4 g , 9 mmol, 1.0 eq) After the dropwise addition, the reaction mixture was stirred for 16 hours, and the temperature was allowed to warm to room temperature during this period. The reaction product was quenched with 1 M HCl (50 mL), extracted with EA (100 mL), the organic layer was dried and concentrated and the residue was purified on silica gel (EA / PE: 20-40% Compound 90-C-4 (1.9 g) was obtained as an oil. MS: Calcd. 415 (MH + ), Measurement 415 (MH + ).
단계 5: THF(20 mL) 중 화합물 90-C-4(1.86 g, 4.5 mmol, 1.0 당량) 및 TBAF(1 M, 9 mL, 2.0 당량)의 용액을 실온에서 2 시간 동안 교반하고, EA(50 mL)로 희석하고, 물(50 mL) 및 염수(50 mL)로 세척하고, 유기 층을 Na2SO4로 건조하고 농축하고, 잔사를 실리카 겔(EA/PE: 30% 내지 70%)로 정제하여 무색 오일로서 화합물 90-C-5(1.2 g)를 수득하였다. MS: 계산치 301(MH+), 측정치 301(MH+). Step 5: A solution of 90-C-4 (1.86 g, 4.5 mmol, 1.0 eq.) And TBAF (1 M, 9 mL, 2.0 eq.) In THF (20 mL) was stirred at room temperature for 2 hours and EA diluted with 50 mL), water (50 mL) and washed with brine (50 mL), dry the organic layer with Na 2 SO 4 and concentrated, and the residue was purified by silica gel (EA / PE: 30% to 70%) To give compound 90-C-5 (1.2 g) as a colorless oil. MS: Calcd 301 (MH + ), found 301 (MH + ).
단계 6: THF(20 mL) 중 화합물 90-C-5(0.9 g, 3 mmol, 1.0 당량), PPh3(1.57 g, 6 mmol, 2.0 당량) 및 이미다졸(0.41 g, 6 mmol, 2.0 당량)의 용액을 1 시간 동안 환류한 후, 요오드(1.3 g, 4.5 mmol, 1.5 당량)를 첨가하고, 2 시간 동안 환류하였다. 이어서, 반응 생성물을 EA(50 mL)로 희석하고, 물(50 mL) 및 염수(50 mL)로 세척하고, 유기 층을 Na2SO4로 건조하고 농축하고, 잔사를 실리카 겔(EA/PE: 0% 내지 25%)로 정제하여 무색 오일로서 화합물 90-C-6(0.61 g)을 수득하였다. MS: 계산치 411(MH+), 측정치 411(MH+). Step 6: THF (20 mL) of compound 90-C-5 (0.9 g , 3 mmol, 1.0 equiv), PPh 3 (1.57 g, 6 mmol, 2.0 eq.) And imidazole (0.41 g, 6 mmol, 2.0 eq. ) Was refluxed for 1 hour, then iodine (1.3 g, 4.5 mmol, 1.5 eq.) Was added and refluxed for 2 hours. Then diluting the reaction product with EA (50 mL), washed with water (50 mL) and brine (50 mL), dried the organic layer with Na 2 SO 4 and concentrated, and the residue was purified by silica gel in (EA / PE : 0% to 25%) to obtain Compound 90-C-6 (0.61 g) as a colorless oil. MS: calculated value 411 (MH + ), measured value 411 (MH + ).
단계 7: DMSO(10 mL) 중 화합물 90-C-6(0.61 g, 1.5 mmol, 1.0 당량) 및 KCN(0.195 g, 3 mmol, 2.0 당량)의 혼합물을 80℃에서 16 시간 동안 교반하였다. 이어서, 반응 생성물을 EA(50 mL)로 희석하고, 물(50 mL) 및 염수(50 mL)로 세척하고, 유기 층을 Na2SO4로 건조하고, 농축하고, 잔사를 실리카 겔(EA/PE: 0% 내지 25%)로 정제하여 무색 오일로서 화합물 90-C-7(0.41 g)을 수득하였다. MS: 계산치 310(MH+), 측정치 310(MH+). Step 7: A mixture of 90-C-6 (0.61 g, 1.5 mmol, 1.0 eq) and KCN (0.195 g, 3 mmol, 2.0 eq) in DMSO (10 mL) was stirred at 80 <0> C for 16 h. The reaction product was then diluted with EA (50 mL), washed with water (50 mL) and brine (50 mL), the organic layer was dried over Na 2 SO 4 , concentrated and the residue was purified on silica gel (EA / PE: 0% to 25%) to obtain Compound 90-C-7 (0.41 g) as a colorless oil. MS: Calculated 310 (MH + ), found 310 (MH + ).
단계 8: HCl/MeOH(3 M, 10 mL) 중 화합물 90-C-7(0.41 g, 1.3 mmol, 1.0 당량)의 혼합물을 80℃에서 16 시간 동안 교반하였다. 이어서, 반응 생성물을 농축하여 백색 고체로서 화합물 90-C(0.36 g)를 수득하였다. MS: 계산치 243(MH+), 측정치 243(MH+). Step 8: A mixture of 90-C-7 (0.41 g, 1.3 mmol, 1.0 eq) in HCl / MeOH (3 M, 10 mL) was stirred at 80 <0> C for 16 hours. The reaction product was then concentrated to give 0.36 g of compound 90-C as a white solid. MS: Calculated 243 (MH < + & gt ; ), found 243 (MH < + & gt ; ).
실시예 91A 및 91B(분리된 2개의 단일 이성질체)Examples 91A and 91B (two isolated isomers)
(8R,8aS)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-2-t-부틸-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-
실시예 91A 및 91B의 제조Preparation of Examples 91A and 91B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 메틸 2-메틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 91-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- Example 82A was prepared using 2-methyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [l, 5-a] pyrazine-8-carboxylate (Compound 91- Two title compounds were prepared analogously to 82B.
연황색 고체로서 실시예 91A(26 mg)를 수득하였다. 1H NMR(400MHz, MeOD) 7.97(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.36-7.26(m, 2H), 7.22-7.11(m, 1H), 6.25(s, 1H), 4.30(d, J = 17.3 Hz, 1H), 4.04(q, J = 7.2 Hz, 2H), 3.95-3.82(m, 3H), 3.61-3.45(m, 2H), 3.31-3.11(m, 2H), 2.93-2.81(m, 4H), 2.49(br, 1H), 1.13(t, J = 7.0 Hz, 3H). LC/MS: 계산치 577(MH+), 측정치 577(MH+).Example 91A (26 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) 7.97 (d, J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.36-7.26 (m, 2H), 7.22-7.11 (m, 1H), 6.25 (s, 1H), 4.30 (d, J = 17.3 Hz, 1H), 4.04 (q, J = 7.2 Hz, 2H), 3.95-3.82 (m, 3H), 3.61-3.45 (m, 2H), 3.31 2H), 2.93-2.81 (m, 4H), 2.49 (br, 1H), 1.13 (t , J = 7.0 Hz, 3H). LC / MS: calculated 577 (MH + ), found 577 (MH + ).
연황색 고체로서 실시예 91B(38 mg)를 수득하였다. 1H NMR(400MHz, MeOD) 7.96(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.39-7.25(m, 2H), 7.17(td, J = 2.0, 7.5, 9.1 Hz, 1H), 6.21(s, 1H), 4.24(d, J = 16.8 Hz, 1H), 4.04(q, J = 7.1 Hz, 2H), 3.98-3.78(m, 3H), 3.60-3.42(m, 2H), 3.31-3.16(m, 2H), 3.04(d, J = 10.3 Hz, 1H), 2.83(s, 3H), 2.61(br, 1H), 1.12(t, J = 7.0 Hz, 3H). LC/MS: 계산치 577(MH+), 측정치 577(MH+).Example 91B (38 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) 7.96 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.39-7.25 (m, 2H), 7.17 (td, J = 2.0, 7.5 , 9.1 Hz, 1H), 6.21 (s, 1H), 4.24 (d, J = 16.8 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98-3.78 (m, 3H), 3.60-3.42 (m, 2H), 3.31-3.16 ( m, 2H), 3.04 (d, J = 10.3 Hz, 1H), 2.83 (s, 3H), 2.61 (br, 1H), 1.12 (t, J = 7.0 Hz, 3H). LC / MS: calculated 577 (MH + ), found 577 (MH + ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 91A-1로부터 실시예 91A를 합성하고(더 빠른 용리) 화합물 91B-1로부터 실시예 91B를 합성하였다(더 느린 용리).Example 91A was synthesized from Compound 91A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 Slow elution).
메틸 2-메틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 91-C)의 제조Preparation of methyl 2-methyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 91-
사이클로프로필아민 대신에 메틸 아민을 사용하여 화합물 82-C와 유사하게 화합물 91-C를 제조하였다.Compound 91-C was prepared similarly to compound 82-C using methylamine instead of cyclopropylamine.
실시예 92A 및 92B(분리된 2개의 단일 이성질체)Examples 92A and 92B (two isolated isomers)
메틸 (4R)-6-[[(8R,8aS)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; 및Methyl (4R) -6 - [[(8R, 8aS) -2-t- butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate; And
메틸 (4R)-6-[[(8S,8aR)-2-t-부틸-8-카바모일-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl (4R) -6 - [[(8S, 8aR) -2-t-butyl-8-carbamoyl-3-oxo-5,6,8,8a-tetrahydro- a] pyrazin-7-yl] methyl] -4- (2-chloro-4-fluoro-phenyl) -2-thiazol-
실시예 92A 및 92B의 제조Preparation of Examples 92A and 92B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-2-t-부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복스아미드(화합물 92-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다. 조질 생성물을 HPLC로 정제하여 2개 이성질체의 혼합물을 수득하고, 이를 SFC로 추가 용해하여 키랄팩 AD-3 컬럼에서 30% 이소프로판올(0.05% DEA)/CO2를 사용하여 2개의 단일 이성질체 92A(더 빠른 용리) 및 92B(더 느린 용리)를 수득하였다.Instead of trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- the -2- t- butyl-3-oxo-hexahydro--1,5,6,7,8,8a- already using imidazo [1,5-a] pyrazin-8-carboxamide (compound 92-C) Two title compounds were prepared analogously to Examples 82A and 82B. The crude product was purified by HPLC to give a mixture of the two isomers which were further dissolved in SFC to give two single isomers 92A (more) using 30% isopropanol (0.05% DEA) / CO 2 on a Chiralpak AD- Fast elution) and 92B (slower elution).
연황색 고체로서 실시예 92A(30 mg)를 수득하였다. 1H NMR(400MHz, MeOD) δ 7.97(d, J = 3.0 Hz, 1H), 7.74(d, J = 3.3 Hz, 1H), 7.37-7.21(m, 2H), 7.20-7.08(m, 1H), 6.20(s, 1H), 4.18(d, J = 17.1 Hz, 1H), 4.02(q, J = 7.0 Hz, 2H), 3.84-3.72(m, 3H), 3.55(t, J = 8.8 Hz, 2H), 3.14(dt, J = 3.5, 12.7 Hz, 1H), 3.05(d, J = 9.3 Hz, 1H), 3.00-2.89(m, 1H), 2.45(dt, J = 3.5, 11.9 Hz, 1H), 1.40(s, 9H), 1.12(t, J = 7.2 Hz, 3H). MS: 계산치 618(MH+), 측정치 618(MH+).Example 92A (30 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ 7.97 (d, J = 3.0 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.37-7.21 (m, 2H), 7.20-7.08 (m, 1H) , 6.20 (s, 1H), 4.18 (d, J = 17.1 Hz, 1H), 4.02 (q, J = 7.0 Hz, 2H), 3.84-3.72 (m, 3H), 3.55 (t, J = 8.8 Hz, 2H), 3.14 (dt, J = 3.5, 12.7 Hz, 1H), 3.05 (d, J = 9.3 Hz, 1H), 3.00-2.89 (m, 1H), 2.45 (dt, J = 3.5, 11.9 Hz, 1H ), 1.40 (s, 9H), 1.12 (t , J = 7.2 Hz, 3H). MS: Calculated 618 (MH < + & gt ; ), found 618 (MH < + & gt ; ).
연황색 고체로서 실시예 92B(30 mg)를 수득하였다. 1H NMR(400MHz, MeOD) δ 7.98(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.36-7.23(m, 2H), 7.20-7.09(m, 1H), 6.25(s, 1H), 4.24(d, J = 17.3 Hz, 1H), 4.04(q, J = 7.1 Hz, 2H), 3.85-3.68(m, 3H), 3.57(t, J = 8.8 Hz, 1H), 3.37-2.35(m, 1H), 3.20-2.99(m, 2H), 2.85-2.69(m, 1H), 2.32(dt, J = 3.4, 12.0 Hz, 1H), 1.49-1.34(s, 9H), 1.13(t, J = 7.0 Hz, 3H). MS: 계산치 618(MH+), 측정치 618(MH+).Example 92B (30 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ 7.98 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.36-7.23 (m, 2H), 7.20-7.09 (m, 1H) , 6.25 (s, 1H), 4.24 (d, J = 17.3 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.85-3.68 (m, 3H), 3.57 (t, J = 8.8 Hz, J = 3.4, 12.0 Hz, 1H), 1.49-1.34 (s, 1H), 3.37-2.35 (m, 9H), 1.13 (t , J = 7.0 Hz, 3 H). MS: Calculated 618 (MH < + & gt ; ), found 618 (MH < + & gt ; ).
트랜스Trance -- 2-2- t-t- 부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복스아미드(화합물 92-C)의 제조Butyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxamide (Compound 92-C)
단계 1: THF(5 mL) 중 화합물 92-C-1(355 mg, 1 mmol)의 용액에 물(1 mL) 중 리튬 하이드록사이드 일수화물(124 mg, 3 mmol)을 첨가하였다. 반응 혼합물을 35℃에서 2 시간 동안 교반한 후, 이를 1 N 하이드로클로라이드 용액으로 pH 3.0으로 중성화하였다. 혼합물을 에틸 아세테이트(30 mL)로 3회 추출하였다. 합한 유기 상을 Na2SO4로 건조한 후, 여과하고 농축하여 백색 고체로서 화합물 92-C-2(340 mg)를 수득하였다. MS: 계산치 356(MH+), 측정치 356(MH+). Step 1: To a solution of 92-C-1 (355 mg, 1 mmol) in THF (5 mL) was added lithium hydroxide monohydrate (124 mg, 3 mmol) in water (1 mL). The reaction mixture was stirred at 35 < 0 > C for 2 hours, then it was neutralized to pH 3.0 with 1 N hydrochloride solution. The mixture was extracted three times with ethyl acetate (30 mL). After drying of the combined organic phases with Na 2 SO 4, filtered and concentrated to give 92-C-2 (340 mg ) as a white solid. MS: Calculated 356 (MH < + & gt ; ), found 356 (MH < + & gt ; ).
단계 2: THF(10 mL) 중 화합물 92-C-2(340 mg, 1 mmol), HATU(380 mg, 1 mmol), NH4Cl(275 mg, 5 mmol) 및 DIPEA(775 mg, 6 mmol)의 혼합물을 50℃에서 2 시간 동안 교반하였다. 이어서, 용해되지 않은 물질을 여과 제거하고 여액을 농축하였다. 잔사를 실리카 겔(EA/PE: 0% 내지 40%)로 정제하여 백색 고체로서 화합물 92-C-3(200 mg)을 수득하였다. MS: 계산치 355(MH+), 측정치 355(MH+). Step 2: the compound 92-C-2 THF (10 mL) (340 mg, 1 mmol), HATU (380 mg, 1 mmol), NH 4 Cl (275 mg, 5 mmol) and DIPEA (775 mg, 6 mmol ) Was stirred at 50 < 0 > C for 2 hours. The undissolved material was then filtered off and the filtrate was concentrated. The residue was purified by silica gel (EA / PE: 0% to 40%) to give compound 92-C-3 (200 mg) as a white solid. MS: Calculated 355 (MH < + & gt ; ), found 355 (MH < + & gt ; ).
단계 3: DCM/TFA(5 mL, 2:1) 중 화합물 92-C-3(200 mg, 0.6 mmol)의 혼합물을 실온에서 2 시간 동안 교반한 후, 혼합물을 감압하에 농축하여 연황색 오일로서 화합물 92-C(200 mg)를 수득하고, 이를 다음 단계에서 직접 사용하였다. MS: 계산치 255(MH+), 측정치 255(MH+). Step 3: The mixture of compound 92-C-3 (200 mg, 0.6 mmol) in DCM / TFA (5 mL, 2: 1) was stirred at room temperature for 2 hours and then the mixture was concentrated under reduced pressure to give Compound 92-C (200 mg) was obtained, which was used directly in the next step. MS: calculated value 255 (MH + ), measured value 255 (MH + ).
트랜스-7-Trans-7- t-t- 부틸-8-메틸 2-Butyl-8-methyl-2- t-t- 부틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7,8-다이카복실레이트(화합물 92-C-1)의 제조Preparation of butyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [l, 5-a] pyrazine-7,8-dicarboxylate (Compound 92-
사이클로프로필아민 대신에 t-부틸아민을 사용하여 화합물 82-C-5와 유사하게 화합물 92-C-1을 제조하였다.Compound 92-C-1 was prepared similarly to compound 82-C-5 using t- butylamine instead of cyclopropylamine.
실시예 93Example 93
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-프로폭시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산3-fluoro-phenyl) -5-propoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-propanoic acid
실시예 93의 제조Preparation of Example 93
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-프로폭시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 C-6) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 93(6 mg)을 수득하였다. 1H NMR(400MHz, MeOD) δ 7.96(d, J = 3.0 Hz, 1H), 7.75(d, J = 3.0 Hz, 1H), 7.34-7.21(m, 2H), 7.15(dt, J = 1.6, 8.5 Hz, 1H), 6.24(s, 1H), 4.19-4.06(m, 1H), 4.03-3.81(m, 5H), 3.51(t, J = 8.9 Hz, 1H), 3.45-3.37(m, 1H), 3.33-3.29(m, 1H), 3.25-3.15(m, 1H), 3.11(dd, J = 4.0, 9.5 Hz, 1H), 2.97-2.78(m, 2H), 2.41-2.29(m, 1H), 2.19(t, J = 10.9 Hz, 1H), 1.59-1.47(m, 2H), 1.21(d, J = 2.8 Hz, 6H), 0.76(t, J = 7.4 Hz, 3H). MS: 계산치 633(MH+), 측정치 633(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (8aS) -7 - [[(4R) -4- (4-methylpiperazin-1-yl) (2-chloro-3-fluoro-phenyl) -5-propoxycarbonyl-2-thiazol-2-yl-1,4- dihydropyrimidin- (Compound C-6) and 3 - [(8aS) -7,8,8a-tetrahydro- lH-imidazo [1,5- a] pyrazin- 5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl-propanoic acid (Compound Q) The title compound was prepared in analogy to example 1. < RTI ID = 0.0 > Example 93 (6 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ 7.96 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.34-7.21 (m, 2H), 7.15 (dt, J = 1.6, 1H), 3.45-3.37 (m, 1H, < RTI ID = 0.0 > ), 3.33-3.29 (m, 1H), 3.25-3.15 (m, 1H), 3.11 (dd , J = 4.0,9.5 Hz, ), 2.19 (t , J = 10.9 Hz, 1H), 1.59-1.47 (m, 2H), 1.21 (d , J = 2.8 Hz, 6H), 0.76 (t , J = 7.4 Hz, 3H). MS: Calcd: 633 (MH + ), Found 633 (MH + ).
프로필 (profile ( 44 R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate (( 화합물 C-6)의 제조Preparation of Compound C-6)
메틸 아세토아세테이트 대신에 n-프로필 아세토아세테이트를 사용하여 화합물 C와 유사하게 화합물 C-6을 제조하였다.Compound C-6 was prepared analogously to compound C using n -propyl acetoacetate instead of methyl acetoacetate.
실시예 94Example 94
4-[(8aS)-7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-부탄산Chloro-4-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol-2-yl-1,4- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- Methyl-butanoic acid
실시예 94의 제조Preparation of Example 94
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-1) 및 (3R)-3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]부탄산 TFA 염(화합물 54-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 57(48 mg)을 수득하였다. 1H NMR(MeOD, 400MHz): δ 7.97(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.02-7.39(m, 3H), 6.24(s, 1H), 3.99-4.16(m, 2H), 3.73-3.95(m, 3H), 3.47(t, J = 9.0 Hz, 2H), 3.02-3.25(m, 3H), 2.68-2.97(m, 2H), 2.10-2.48(m, 3H), 1.76(br. s., 2H), 1.23(s, 6H), 1.13 ppm(t, J = 7.2 Hz, 3H). MS: 계산치 633(MH+), 측정치 633(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-1) and (3R) -3 - [(8aS) -2-thiazol-2-yl-1,4-dihydropyrimidine- Yl) butanoic acid TFA salt (Compound 54-A) was used instead of 3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- , The title compound was prepared. Example 57 (48 mg) was obtained as a light yellow solid. 1 H NMR (MeOD, 400MHz) : δ 7.97 (d, J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.02-7.39 (m, 3H), 6.24 (s, 1H), 3.99-4.16 (m, 2H), 3.73-3.95 (m, 3H), 3.47 (t, J = 9.0 Hz, 2H), 3.02-3.25 (m, 3H), 2.68-2.97 (m, 2H), 2.10- 2.48 (m, 3H), 1.76 (br s, 2H), 1.23 (s, 6H), 1.13 ppm (t, J = 7.2 Hz, 3H). MS: Calcd: 633 (MH + ), Found 633 (MH + ).
실시예 95Example 95
5-[7-[[(4R)-4-(2-클로로-4-플루오로-페닐)-5-메톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]피리딘-2-카복실산5- [7 - [[(4R) -4- (2-Chloro-4-fluoro-phenyl) -5-methoxycarbonyl-2-thiazol- Yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin-
실시예 95의 제조Preparation of Example 95
헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 5-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)피리딘-2-카복실산 TFA 염(화합물 95-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 95(48 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 9.02(s, 1H), 8.17(s, 2H), 8.01(s, 1H), 7.88(s, 1H), 7.51 내지 7.54(m, 1H), 7.30 내지 7.28(m, 1H), 7.10 내지 7.13(m, 1H), 6.20(s, 1H), 4.41-4.63(m, 2H), 4.17-4.35(m, 3H), 3.51-3.75(m, 7 H), 3.01-3.12(m, 2H). MS: 계산치 626(MH+), 측정치 626(MH+).(3-oxo-1,5,6,7,8,8a-hexahydro-pyrazino [l, 2-c] [1,3] oxazin- Carboxylic acid TFA salt (Compound 95-A), the title compound was prepared in analogy to example 1. < 1 > Example 95 (48 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 9.02 (s , 1H), 8.17 (s, 2H), 8.01 (s, 1H), 7.88 (s, 1H), 7.51 to 7.54 (m, 1H) 2H), 4.17-4.35 (m, 3H), 3.51-3.75 (m, 2H), 7.30-7.23 (m, 7 H), 3.01-3.12 (m, 2H). MS: Calculated 626 (MH < + & gt ; ), found 626 (MH < + & gt ; ).
5-(3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일)피리딘-2-카복실산(화합물 95-A)의 제조Preparation of 5- (3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl) pyridine-2-carboxylic acid (Compound 95-
단계 1: MeOH(30 mL) 중 5-브로모피리딘-2-카복실산(5.0 g, 24.75 mmol)의 용액을 0℃에서 티온일 클로라이드(10 mL)에 적가하였다. 이어서, 혼합물을 60℃에서 12 시간 동안 교반하였다. 용매 및 티온일 클로라이드 잔사를 제거한 후, 조질 생성물 메틸 5-브로모피리딘-2-카복실레이트를 수득하고 추가 정제 없이 다음 단계에서 사용하였다. Step 1: A solution of 5-bromopyridine-2-carboxylic acid (5.0 g, 24.75 mmol) in MeOH (30 mL) was added dropwise at 0 C to thionyl chloride (10 mL). The mixture was then stirred at 60 < 0 > C for 12 hours. After removal of the solvent and thionylchloride residues, the crude product methyl 5-bromopyridine-2-carboxylate was obtained and used in the next step without further purification.
단계 2: 다이옥산(3 mL) 중 메틸 5-브로모피리딘-2-카복실레이트(화합물 95-A-1, 0.72 g, 3.28 mmol), t-부틸 3-옥소-1,2,5,6,8,8a-헥사하이드로이미다조[1,5-a]피라진-7-카복실레이트(라세미 화합물 M, 0.40 g, 1.64 mmol), 비스(다이벤질리덴아세톤) 팔라듐(94.4 mg, 0.164 mmol), (±)-2,2'-비스(다이페닐포스피노)-1,1'-바이나프틸(196.8 mg, 0.33 mmol) 및 세슘 카보네이트(160.4 mg, 4.92 mmol)의 혼합물을 130℃에서 3 시간 동안 마이크로파에서 교반하였다. 용매를 제거한 후, 잔사를 컬럼으로 정제하여 백색 고체로서 생성물 95-A-2를 수득하였다. MS: 계산치 377(MH+), 측정치 377(MH+). Step 2: To a solution of methyl 5-bromopyridine-2-carboxylate (Compound 95-A-1, 0.72 g, 3.28 mmol), t- butyl 3- (Racemic compound M, 0.40 g, 1.64 mmol), bis (dibenzylideneacetone) palladium (94.4 mg, 0.164 mmol) in tetrahydrofuran A mixture of (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (196.8 mg, 0.33 mmol) and cesium carbonate (160.4 mg, 4.92 mmol) Lt; / RTI > After removal of the solvent, the residue was purified by column to give the product 95-A-2 as a white solid. MS: Calculated 377 (MH < + & gt ; ), found 377 (MH < + & gt ; ).
단계 3: 물(2 mL) 및 MeOH(5 mL) 중 화합물 95-A-2(0.24 g, 0.64 mmol) 및 리튬 하이드록사이드(0.13 g, 3.2 mmol)의 혼합물을 실온에서 12 시간 동안 교반하였다. 이어서, 반응 혼합물을 1 N HCl로 pH 6으로 중성화하고, 에틸 아세테이트로 추출하였다. 유기 층을 나트륨 설페이트로 건조하였다. 용매를 제거한 후, 잔사를 DCM(10 mL) 중 TFA(2 mL)로 처리하였다. 반응 혼합물을 30 분 동안 교반한 후, 용매를 제거하여 조질 생성물을 수득하고, 이를 다음 단계에서 직접 사용하였다. MS: 계산치 263(MH+), 측정치 263(MH+). Step 3: A mixture of compound 95-A-2 (0.24 g, 0.64 mmol) and lithium hydroxide (0.13 g, 3.2 mmol) in water (2 mL) and MeOH (5 mL) was stirred at room temperature for 12 hours . The reaction mixture was then neutralized to pH 6 with 1 N HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After removal of the solvent, the residue was treated with TFA (2 mL) in DCM (10 mL). The reaction mixture was stirred for 30 minutes and then the solvent was removed to give the crude product which was used directly in the next step. MS: Calculated 263 (MH < + & gt ; ), found 263 (MH < + & gt ; ).
실시예 96Example 96
(S)-6-[(S)-2-(2-카복시-2,2-다이플루오로-에틸)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-7-일메틸]-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 에틸 에스터(S) -6- [(S) -2- (2-carboxy-2,2-difluoro-ethyl) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Methyl-4- (3,4-difluoro-2-methyl-phenyl) -2-thiazol-2-yl-1,4- dihydro-pyrimidine-
실시예 96의 제조Preparation of Example 96
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-7) 및 2,2-다이플루오로-3-((S)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-2-일)-프로피온산 트라이플루오로아세테이트 염(화합물 96-A)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 96(15 mg)을 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 8.01(d, 1H), 7.90(d, 1H), 7.26(m, 1H), 7.07-7.15(m, 1H), 5.94-5.98(m, 1H), 4.69(d, 1H), 4.51(d, 1H), 4.05-4.20(m, 4H), 3.86-3.98(m, 2H), 3.62-3.80(m, 4H), 3.41-3.52(m, 1H), 3.07-3.22(m, 3H), 2.52(d, 3H), 1.15(m, 3H). MS: 계산치 625(MH+), 측정치 625(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4S) -6- (bromomethyl) -4- (3-tert-butoxycarbonylamino) propionic acid in place of the compound C) and hexahydro-pyrazino [ Methyl-phenyl) -2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (Compound C-7) and 2,2-difluoro -Propionic acid trifluoroacetate salt (Compound 96-A) was used instead of (S) -3-oxo-hexahydro-imidazo [1,5- a] pyrazin- The title compound was prepared analogously. Example 96 (15 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 8.01 (d , 1H), 7.90 (d, 1H), 7.26 (m, 1H), 7.07-7.15 (m, 1H), 5.94-5.98 (m, 2H), 3.62-3.80 (m, 4H), 3.41-3.52 (m, 2H), 4.69 (d, 1H), 3.07-3.22 (m, 3H), 2.52 (d, 3H), 1.15 (m, 3H). MS: Calculated 625 (MH < + & gt ; ), found 625 (MH < + & gt ; ).
2,2-다이플루오로-3-((S)-3-옥소-헥사하이드로-이미다조[1,5-a]피라진-2-일)-프로피온산 트라이플루오로아세테이트 염(화합물 96-A)의 제조(Compound 96-A) was reacted with 2,2-difluoro-3 - ((S) -3-oxo-hexahydro- imidazo [1,5- a] pyrazin- Manufacturing
단계 1: DCM(5 mL) 중 3-아미노-2,2-다이플루오로-프로피온산 하이드로클로라이드 염(400 mg, 1.10 mmol)의 교반된 용액에 0℃에서 DIPEA(142 mg, 1.10 mmol)를 첨가하고, DCM(5 mL) 중 화합물 S(350 mg, 1 mmol)의 용액을 연속하여 첨가하였다. 반응 혼합물을 0℃에서 5 분 동안 교반하였다. 이어서, NaBH(OAc)3을 상기 혼합물에 첨가하였다. 생성된 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물을 DCM과 물 사이에 분배하였다. 유기 층을 분리하고, Na2SO4로 건조하고, 진공에서 농축하고 단리하여 화합물 96-A-1(320 mg)을 수득하였다. Step 1: To a stirred solution of 3-amino-2,2-difluoro-propionic acid hydrochloride salt (400 mg, 1.10 mmol) in DCM (5 mL) at 0 C was added DIPEA (142 mg, 1.10 mmol) And a solution of compound S (350 mg, 1 mmol) in DCM (5 mL) was added successively. The reaction mixture was stirred at 0 < 0 > C for 5 minutes. NaBH (OAc) 3 was then added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between DCM and water. The organic layer was separated, dried over Na 2 SO 4 , concentrated in vacuo and isolated to give 320 mg of compound 96-A-1.
단계 2: MeOH(5 mL) 중 화합물 96-A-1(320 mg, 0.70 mmol) 및 Pd/C(30 mg)의 혼합물을 수소 풍선으로 실온에서 밤새 교반하였다. 반응 혼합물을 여과하고 여액을 농축하였다. 조질 생성물 96-A-2(226 mg)를 수득하고 추가 정제 없이 다음 단계에서 사용하였다. Step 2: A mixture of compound 96-A-1 (320 mg, 0.70 mmol) and Pd / C (30 mg) in MeOH (5 mL) was stirred overnight at room temperature with a balloon of hydrogen. The reaction mixture was filtered and the filtrate was concentrated. The crude product 96-A-2 (226 mg) was obtained and used in the next step without further purification.
단계 3: 다이클로로메탄(3 ml) 중 화합물 96-A-2(조질, 226 mg, 0.70 mmol)의 용액에 0℃에서 DIPEA(0.6 mL, 3.50 mmol)를 첨가한 후, 트라이포스겐(103 mg, 0.35 mmol)을 상기 반응 혼합물에 첨가하였다. 생성된 혼합물을 실온으로 가온하고 밤새 교반하였다. 반응 혼합물을 농축하고, 잔사를 다음 단계에서 직접 사용하였다. 조질 생성물 96-A-3의 양은 340 mg이었다. Step 3: To a solution of 96-A-2 (crude, 226 mg, 0.70 mmol) in dichloromethane (3 ml) at 0 C was added DIPEA (0.6 mL, 3.50 mmol) followed by triphosgene , 0.35 mmol) was added to the reaction mixture. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the residue was used directly in the next step. The amount of crude product 96-A-3 was 340 mg.
단계 4: 다이클로로메탄(2 mL) 중 화합물 96-A-3(조질, 340 mg, 0.70 mmol)의 용액에 실온에서 트라이플루오로아세트산(5 mL)을 첨가하였다. 반응 혼합물을 1.5 시간 동안 교반한 후, 용매를 제거하여 조질 생성물 96-A(260 mg)를 수득하고, 이를 다음 단계에서 직접 사용하였다. Step 4: To a solution of 96-A-3 (crude, 340 mg, 0.70 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (5 mL) at room temperature. The reaction mixture was stirred for 1.5 hours and then the solvent was removed to give crude product 96-A (260 mg) which was used directly in the next step.
에틸 (4S)-6-(브로모메틸)-4-(3,4-다이플루오로-2-메틸-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-7)의 제조Ethyl (4S) -6- (bromomethyl) -4- (3,4-difluoro-2-methyl-phenyl) -2-thiazol-2-yl-1,4-dihydropyrimidine- - < / RTI > carboxylate (Compound C-7)
2-클로로-4-플루오로벤즈알데하이드 및 메틸 아세토아세테이트 대신에 3,4-다이플루오로-2-메틸벤즈알데하이드 및 에틸 아세토아세테이트를 사용하여 화합물 C와 유사하게 화합물 C-7을 제조하였다.Compound C-7 was prepared similarly to compound C using 3,4-difluoro-2-methylbenzaldehyde and ethyl acetoacetate instead of 2-chloro-4-fluorobenzaldehyde and methyl acetoacetate.
실시예 97A 및 97B(분리된 2개의 단일 이성질체)Examples 97A and 97B (two isolated isomers)
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid ; And
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(사이클로프로필메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2- (cyclopropylmethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예 97A 및 97B의 제조Preparation of Examples 97A and 97B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-메틸 2-(사이클로프로필메틸)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 97-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- - a-methyl-2- (cyclopropylmethyl) -3-oxo -1,5,6,7,8,8a- hexahydro-imidazo [1,5-a] pyrazin-8-carboxylate (compound 97-C) , The title compound was prepared in analogy to example 82A and 82B.
연황색 고체로서 실시예 97A(25 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98(d, J = 3.0 Hz, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.35-7.26(m, 2H), 7.20-7.11(m, 1H), 6.25(s, 1H), 4.30(s, 1H), 4.10-3.99(m, 2H), 3.95-3.86(m, 2H), 3.81(d, J = 11.5 Hz, 1H), 3.68(d, J = 8.0 Hz, 1H), 3.65-3.58(m, 1H), 3.37-3.34(m, 2H), 3.25-3.16(m, 1H), 3.25-3.16(m, 1H), 3.15-3.07(m, 2H), 2.91(d, J = 11.5 Hz, 1H), 2.60-2.49(m, 1H), 1.13(t, J = 7.2 Hz, 3H), 1.03-0.93(m, 1H), 0.61-0.53(m, 2H), 0.28-0.23(m, 2H). MS: 계산치 617(MH+), 측정치 617(MH+).Example 97A (25 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98 (d , J = 3.0 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.35-7.26 (m, 2H), 7.20-7.11 (m, 2H), 3.81 (d , J = 11.5 Hz, 1H), 6.30 (s, 3.68 (d, J = 8.0 Hz , 1H), 3.65-3.58 (m, 1H), 3.37-3.34 (m, 2H), 3.25-3.16 (m, 1H), 3.25-3.16 (m, 1H), 3.15- 3.07 (m, 2H), 2.91 (d, J = 11.5 Hz, 1H), 2.60-2.49 (m, 1H), 1.13 (t, J = 7.2 Hz, 3H), 1.03-0.93 (m, 1H), 0.61 -0.53 (m, 2H), 0.28-0.23 (m, 2H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
연황색 고체로서 실시예 97B(19 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.33-7.23(m, 3H), 7.15(t, J = 8.3 Hz, 1H), 6.22(s, 1H), 4.12-4.02(m, 3H), 3.95-3.84(m, 3H), 3.52(t, J = 8.9 Hz, 1H), 3.44-3.38(m, 1H), 3.29(s, 1H), 3.24-3.09(m, 2H), 2.93(d, J = 11.0 Hz, 1H), 2.84(d, J = 8.5 Hz, 1H), 2.48(d, J = 0.8 Hz, 3H), 2.37(dt, J = 3.4, 11.6 Hz, 1H), 2.18(t, J = 10.9 Hz, 1H), 1.21(d, J = 3.0 Hz, 6H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 617(MH+), 측정치 617(MH+).Example 97B (19 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.33-7.23 (m , 3H), 7.15 (t, J = 8.3 Hz, 1H), 6.22 (s, 1H), 4.12-4.02 (m, 3H) 2H), 2.93 (m, 2H), 3.95-3.84 (m, 3H), 3.52 (t , J = 8.9 Hz, , J = 11.0 Hz, 1H) , 2.84 (d, J = 8.5 Hz, 1H), 2.48 (d, J = 0.8 Hz, 3H), 2.37 (dt, J = 3.4, 11.6 Hz, 1H), 2.18 (t , J = 10.9 Hz, 1H), 1.21 (d , J = 3.0 Hz, 6H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calculated 617 (MH < + & gt ; ), found 617 (MH < + & gt ; ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 97A-1로부터 실시예 97A를 합성하고(더 빠른 용리) 화합물 97B-1로부터 실시예 97B를 합성하였다(더 느린 용리).Example 97A was synthesized from compound 97A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and Example 97B was synthesized from compound 97B-1 Slow elution).
트랜스Trance -- 메틸 2-(사이클로프로필메틸)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 97-C)의 제조Preparation of methyl 2- (cyclopropylmethyl) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 97-
사이클로프로필아민 대신에 사이클로프로필메탄아민을 사용하여 화합물 82-C와 유사하게 화합물 97-C를 제조하였다.Compound 97-C was prepared similarly to compound 82-C using cyclopropylmethanamine instead of cyclopropylamine.
실시예 98Example 98
3-[(8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-(4-메틸티아졸-2-일)-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(3-fluoro-phenyl) -5-ethoxycarbonyl-2- (4-methylthiazol-2-yl) -1,4-dihydropyrimidin-6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazin- 2,2-dimethyl-propanoic acid
실시예 98의 제조Preparation of Example 98
(R)-6-브로모메틸-4-(2-클로로-4-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로-피리미딘-5-카복실산 메틸 에스터(화합물 C) 및 헥사하이드로-피라지노[1,2-c][1,3]옥사진-6-온(화합물 D) 대신에 에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-(4-메틸티아졸-2-일)-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-8) 및 3-[(8aS)-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-2-일]-2,2-다이메틸-프로판산(화합물 Q)을 사용하여 실시예 1과 유사하게 표제 화합물을 제조하였다. 연황색 고체로서 실시예 93(60 mg)을 수득하였다. 1H NMR(400MHz, MeOD) δ 7.33-7.23(m, 3H), 7.15(t, J = 8.3 Hz, 1H), 6.22(s, 1H), 4.12-4.02(m, 3H), 3.95-3.84(m, 3H), 3.52(t, J = 8.9 Hz, 1H), 3.44-3.38(m, 1H), 3.29(s, 1H), 3.24-3.09(m, 2H), 2.93(d, J = 11.0 Hz, 1H), 2.84(d, J = 8.5 Hz, 1H), 2.48(d, J = 0.8 Hz, 3H), 2.37(dt, J = 3.4, 11.6 Hz, 1H), 2.18(t, J = 10.9 Hz, 1H), 1.21(d, J = 3.0 Hz, 6H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 633(MH+), 측정치 633(MH+). (R) -6- bromo-4- (2-chloro-4-fluoro-phenyl) -2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester ( (4R) -6- (bromomethyl) -4- (2-methoxyphenyl) propionic acid ethyl ester was used in the place of compound C) and hexahydro-pyrazino [ (Compound C-8) and 3 - [(8aS) -2-methyl-thiazol- ) -3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-2-yl] -2,2-dimethyl- The title compound was prepared in analogy to example 1. < RTI ID = 0.0 > Example 93 (60 mg) was obtained as a light yellow solid. 1 H NMR (400MHz, MeOD) δ 7.33-7.23 (m, 3H), 7.15 (t, J = 8.3 Hz, 1H), 6.22 (s, 1H), 4.12-4.02 (m, 3H), 3.95-3.84 ( m, 3H), 3.52 (t , J = 8.9 Hz, 1H), 3.44-3.38 (m, 1H), 3.29 (s, 1H), 3.24-3.09 (m, 2H), 2.93 (d, J = 11.0 Hz , 1H), 2.84 (d, J = 8.5 Hz, 1H), 2.48 (d, J = 0.8 Hz, 3H), 2.37 (dt, J = 3.4, 11.6 Hz, 1H), 2.18 (t, J = 10.9 Hz , 1H), 1.21 (d , J = 3.0 Hz, 6H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calcd: 633 (MH + ), Found 633 (MH + ).
에틸 (4R)-6-(브로모메틸)-4-(2-클로로-3-플루오로-페닐)-2-(4-메틸티아졸-2-일)-1,4-다이하이드로피리미딘-5-카복실레이트(화합물 C-8)의 제조Chloro-3-fluoro-phenyl) -2- (4-methylthiazol-2-yl) -1,4-dihydropyrimidine -5-carboxylate (Compound C-8)
티아졸-2-카보니트릴 및 메틸 아세토아세테이트 대신에 4-메틸티아졸-2-카보니트릴 및 에틸 아세토아세테이트를 사용하여 화합물 C와 유사하게 화합물 C-8을 제조하였다.Compound C-8 was prepared analogously to compound C using 4-methylthiazole-2-carbonitrile and ethyl acetoacetate instead of thiazole-2-carbonitrile and methyl acetoacetate.
실시예 99Example 99
2-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-6-옥소-1,3,4,7,8,8a-헥사하이드로피롤로[1,2-a]피라진-1-카복실산(2개 이성질체의 혼합물)2 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl-2-thiazol- Methyl] -6-oxo-1,3,4,7,8,8a-hexahydropyrrolo [1,2-a] pyrazine-1-carboxylic acid (mixture of two isomers)
실시예 99의 제조Preparation of Example 99
2개의 트랜스 이성질체의 키랄 분리 없이 트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-6-옥소-2,3,4,7,8,8a-헥사하이드로-1H-피롤로[1,2-a]피라진-1-카복실산(화합물 99-A)을 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다. 2개 이성질체의 혼합물로서 실시예 99(연황색 고체, 79 mg)를 수득하였다. 1H NMR(400MHz, MeOD) δ 7.95(d, J = 3.0 Hz, 1H), 7.75(d, J = 3.3 Hz, 1H), 7.35-7.26(m, 2H), 7.17(t, J = 8.2 Hz, 1H), 6.22(s, 1H), 4.25(d, J = 17.1 Hz, 1H), 4.08-4.01(m, 3H), 3.98(s, 2H), 3.20-3.09(m, 3H), 2.61(t, J = 12.7 Hz, 1H), 2.52-2.42(m, 2H), 2.34-2.23(m, 1H), 2.08-1.97(m, 1H), 1.12(t, J = 7.2 Hz, 3H). MS: 계산치 562(MH+), 측정치 562(MH+).Trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 99-A) instead of trans - 6-oxo-2,3,4,7,8,8a-hexahydro-lH-pyrrolo [ , The title compound was prepared in analogy to example 82A and 82B. As a mixture of the two isomers, Example 99 (light yellow solid, 79 mg) was obtained. 1 H NMR (400MHz, MeOD) δ 7.95 (d, J = 3.0 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.35-7.26 (m, 2H), 7.17 (t, J = 8.2 Hz , 1H), 6.22 (s, 1H), 4.25 (d, J = 17.1 Hz, 1H), 4.08-4.01 (m, 3H), 3.98 (s, 2H), 3.20-3.09 (m, 3H), 2.61 ( 1H , J = 12.7 Hz, 1H), 2.52-2.42 (m, 2H), 2.34-2.23 (m, 1H), 2.08-1.97 (m, 1H), 1.12 (t , J = 7.2 Hz, 3H). MS: Calcd. 562 (MH + ), Measurement 562 (MH + ).
트랜스Trance -- 6-옥소-2,3,4,7,8,8a-헥사하이드로-1H-피롤로[1,2-a]피라진-1-카복실산(화합물 99-A)의 제조Preparation of 6-oxo-2,3,4,7,8,8a-hexahydro-lH-pyrrolo [1,2-a] pyrazine-1-carboxylic acid (Compound 99-
단계 1: DCM(100 mL) 중 화합물 82-C-2(12 g, 32.3 mmol)의 교반된 용액에 TEA(6.6 g, 64.5 mmol) 및 (12.3 g, 35.5 mmol)를 첨가하였다. 혼합물을 25℃에서 15 시간 동안 교반하였다. 물(100 mL)을 첨가하고, 혼합물을 DCM(100 mL)으로 추출하였다. 유기 층을 분리하고 Na2SO4로 건조하였다. 용매를 제거하고, 잔사를 컬럼으로 정제하여 화합물 99-A-1(10 g)을 수득하였다. 1H NMR(400MHz, CDCl3) δ 4.90-4.76(m, 1H), 4.71-4.48(m, 1H), 4.24-4.08(m, 2H), 4.03-3.90(m, 1H), 3.85-3.71(m, 5H), 3.21-2.87(m, 2H), 2.31(dq, J = 8.5, 16.5 Hz, 2H), 2.22-2.05(m, 1H), 1.98-1.80(m, 1H), 1.57-1.40(m, 21H), 1.33-1.23(m, 3H). Step 1 : To a solution of < RTI ID = 0.0 > To the stirred solution of 82-C-2 (12 g, 32.3 mmol) was added TEA (6.6 g, 64.5 mmol) and (12.3 g, 35.5 mmol). The mixture was stirred at 25 < 0 > C for 15 hours. Water (100 mL) was added and the mixture was extracted with DCM (100 mL). The organic layer was separated and dried over Na 2 SO 4. The solvent was removed and the residue was purified by column to give compound 99-A-1 (10 g). 1 H NMR (400MHz, CDCl 3 ) δ 4.90-4.76 (m, 1H), 4.71-4.48 (m, 1H), 4.24-4.08 (m, 2H), 4.03-3.90 (m, 1H), 3.85-3.71 ( 1H), 1.98-1.80 (m, 1H), 1.57-1.40 (m, 1H), 3.21-2.87 (m, 2H), 2.31 (dq , J = 8.5, 16.5 Hz, 2H) m, 21H), 1.33-1.23 (m, 3H).
단계 2: MeOH(600 mL) 중 화합물 99-A-1(20 g, 45.2 mmol)의 교반된 용액에 Pd/C(10 g)를 첨가하였다. 혼합물을 30℃(50 Psi)에서 15 시간 동안 교반하였다. 혼합물을 여과하고 용매를 진공에서 제거하여 조질 생성물을 수득하고, 이를 컬럼으로 정제하여 화합물 99-A-2(17 g, 조질)를 수득하였다. Step 2 : To a solution of compound < RTI ID = 0.0 > To a stirred solution of 99-A-1 (20 g, 45.2 mmol) was added Pd / C (10 g). The mixture was stirred at 30 < 0 > C (50 Psi) for 15 hours. The mixture was filtered and the solvent removed in vacuo to give a crude product which was purified by column to give compound 99-A-2 (17 g, crude).
단계 3: 무수 DCM(90 mL) 중 화합물 99-A-2(17 g, 38.2 mmol)의 교반된 용액에 TFA(180 mL)를 첨가하였다. 반응 혼합물을 3 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물 99-A-3(19 g, 조질)을 수득하였다. Step 3 : TFA (180 mL) was added to a stirred solution of compound 99-A-2 (17 g, 38.2 mmol) in anhydrous DCM (90 mL). The reaction mixture was stirred for 3 hours and then the solvent was removed in vacuo to give the crude product 99-A-3 (19 g, crude).
단계 4: 무수 DCM(250 mL) 중 화합물 99-A-3(11 g, 25.1 mmol)의 교반된 용액에 DIPEA(16 g, 125.6 mmol)를 첨가하였다. 혼합물을 4 시간 동안 환류한 후, 용매를 제거하여 조질 생성물 99-A(7 g)를 수득하고, 이를 다음 단계에서 직접 사용하였다. Step 4 : DIPEA (16 g, 125.6 mmol) was added to a stirred solution of 99-A-3 (11 g, 25.1 mmol) in anhydrous DCM (250 mL). The mixture was refluxed for 4 hours and then the solvent was removed to give the crude product 99-A (7 g) which was used directly in the next step.
실시예 101A 및 101B(분리된 2개의 단일 이성질체)Examples 101A and 101B (two isolated isomers)
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소부틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- 6-yl] methyl] -2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5-a] pyrazine-8-carboxylic acid; And
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-이소부틸-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -2-isobutyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-8-carboxylic acid
실시예 101A 및 101B의 제조Preparation of Examples 101A and 101B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-메틸 2-이소부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 101-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- -methyl-2-isobutyl-3-oxo-hexahydro--1,5,6,7,8,8a- performed already using imidazo [1,5-a] pyrazin-8-carboxylate (compound C-101) Two title compounds were prepared analogously to Examples 82A and 82B.
연황색 고체로서 실시예 101A(10 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98(d, J = 3.3 Hz, 1H), 7.78(d, J = 3.3 Hz, 1H), 7.34-7.27(m, 2H), 7.19-7.13(m, 1H), 6.25(s, 1H), 4.31(d, J = 17.1 Hz, 1H), 4.09-4.01(m, 2H), 3.94-3.86(m, 2H), 3.83-3.76(m, 1H), 3.60-3.48(m, 2H), 3.29(d, J = 9.5 Hz, 1H), 3.25-3.16(m, 1H), 3.10-2.98(m, 2H), 2.90(d, J = 11.0 Hz, 1H), 2.57-2.45(m, 1H), 1.99-1.88(m, 1H), 1.13(t, J = 7.0 Hz, 3H), 0.95(dd, J = 4.9, 6.7 Hz, 6H). MS: 계산치 619(MH+), 측정치 619(MH+).Example 101A (10 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98 (d , J = 3.3 Hz, 1H), 7.78 (d, J = 3.3 Hz, 1H), 7.34-7.27 (m, 2H), 7.19-7.13 (m, 1H), 6.25 (s, 1H), 4.31 (d , J = 17.1 Hz, 1H), 4.09-4.01 (m, 2H), 3.94-3.86 ), 3.60-3.48 (m, 2H) , 3.29 (d, J = 9.5 Hz, 1H), 3.25-3.16 (m, 1H), 3.10-2.98 (m, 2H), 2.90 (d, J = 11.0 Hz, 1H), 2.57-2.45 (m, 1H), 1.99-1.88 (m, 1H), 1.13 (t , J = 7.0 Hz, 3H), 0.95 (dd , J = 4.9, 6.7 Hz, 6H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
연황색 고체로서 실시예 101B(14 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.36-7.27(m, 2H), 7.19-7.14(m, 1H), 6.21(s, 1H), 4.24(d, J = 16.8 Hz, 1H), 4.07-3.93(m, 3H), 3.92-3.82(m, 2H), 3.59-3.45(m, 2H), 3.29-3.18(m, 2H), 3.03(dd, J = 7.5, 11.0 Hz, 3H), 2.66-2.56(m, 1H), 1.98-1.88(m, 1H), 1.12(t, J = 7.0 Hz, 3H), 0.94(d, J = 6.8 Hz, 6H). MS: 계산치 619(MH+), 측정치 619(MH+).Example 101B (14 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.36-7.27 (m, 2H), 7.19-7.14 (m, 2H), 3.59-3.45 (m, 2H), 6.21 (s, 1H), 4.24 (d , J = 16.8 Hz, 1H), 4.07-3.93 ), 3.29-3.18 (m, 2H) , 3.03 (dd, J = 7.5, 11.0 Hz, 3H), 2.66-2.56 (m, 1H), 1.98-1.88 (m, 1H), 1.12 (t, J = 7.0 Hz, 3H), 0.94 (d , J = 6.8 Hz, 6H). MS: Calculated 619 (MH < + & gt ; ), found 619 (MH < + & gt ; ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 101A-1로부터 실시예 101A를 합성하고(더 빠른 용리) 화합물 101B-1로부터 실시예 101B를 합성하였다(더 느린 용리).Example 101A was synthesized from Compound 101A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and Example 101B was synthesized from Compound 101B-1 Slow elution).
트랜스-메틸 2-이소부틸-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 101-C)의 제조Preparation of trans-methyl 2-isobutyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8-carboxylate (Compound 101-C)
사이클로프로필아민 대신에 2-메틸프로판-1-아민을 사용하여 화합물 82-C와 유사하게 화합물 101-C를 제조하였다.Compound 101-C was prepared similarly to compound 82-C using 2-methylpropan-1-amine instead of cyclopropylamine.
실시예 102A 및 102B(분리된 2개의 단일 이성질체)Examples 102A and 102B (two isolated isomers)
(8R,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산; 및(8R, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- 6-yl] methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid; And
(8S,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-3-옥소-5,6,8,8a-테트라하이드로-1H-옥사졸로[3,4-a]피라진-8-카복실산(8S, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Methyl] -3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo [3,4-a] pyrazine-8-carboxylic acid
실시예 102A 및 102B의 제조Preparation of Examples 102A and 102B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-메틸 3-옥소-1,5,6,7,8,8a-헥사하이드로옥사졸로[3,4-a]피라진-8-카복실레이트(화합물 102-C)를 사용하여 실시예 82A 및 82B와 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans-methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- - methyl 3-oxo -1,5,6,7,8,8a- hexahydro-oxazolo [3,4-a] pyrazin-8-carboxylate in example 82A and 82B using a (compound 102-C) Similarly, two title compounds were prepared.
연황색 고체로서 실시예 102A(29 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.78(d, J = 3.0 Hz, 1H), 7.35-7.27(m, 2H), 7.20-7.13(m, 1H), 6.26(s, 1H), 4.63-4.53(m, 1H), 4.44(dd, J = 6.0, 9.3 Hz, 1H), 4.28(d, J = 17.1 Hz, 1H), 4.15-3.97(m, 4H), 3.77(dd, J = 2.3, 13.3 Hz, 1H), 3.47(d, J = 9.8 Hz, 1H), 3.30(d, J = 3.5 Hz, 1H), 2.96(dd, J = 2.1, 12.2 Hz, 1H), 2.68-2.58(m, 1H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 564(MH+), 측정치 564(MH+).Example 102A (29 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.78 (d, J = 3.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.20-7.13 (m, 1H), 6.26 ( s, 1H), 4.63-4.53 (m, 1H), 4.44 (dd, J = 6.0, 9.3 Hz, 1H), 4.28 (d, J = 17.1 Hz, 1H), 4.15- 3.97 (m, 4H), 3.77 (dd, J = 2.3, 13.3 Hz, 1H), 3.47 (d, J = 9.8 Hz, 1H), 3.30 (d, J = 3.5 Hz, 1H), 2.96 (dd, J = 2.1, 12.2 Hz, 1H), 2.68-2.58 (m, 1H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calcd. 564 (MH + ), Measurement 564 (MH + ).
연황색 고체로서 실시예 102B(27 mg)를 수득하였다. 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.35-7.28(m, 2H), 7.20-7.14(m, 1H), 6.23(s, 1H), 4.61-4.53(m, 1H), 4.40(dd, J = 6.3, 9.3 Hz, 1H), 4.23-4.17(m, 1H), 4.13-4.02(m, 4H), 3.80(dd, J = 2.5, 13.6 Hz, 1H), 3.46(d, J = 9.8 Hz, 1H), 3.39-3.27(m, 1H), 3.08(dd, J = 2.3, 12.3 Hz, 1H), 2.73(dt, J = 3.6, 12.2 Hz, 1H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 564(MH+), 측정치 564(MH+).Example 102B (27 mg) was obtained as a light yellow solid. 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.35-7.28 (m, 2H), 7.20-7.14 (m, 1H), 6.23 (s, 1H), 4.61-4.53 (m, 1H), 4.40 (dd , J = 6.3,9.3 Hz, 1H), 4.23-4.17 , 4H), 3.80 (dd, J = 2.5, 13.6 Hz, 1H), 3.46 (d, J = 9.8 Hz, 1H), 3.39-3.27 (m, 1H), 3.08 (dd, J = 2.3, 12.3 Hz, 1H), 2.73 (dt , J = 3.6, 12.2 Hz, 1H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calcd. 564 (MH + ), Measurement 564 (MH + ).
30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 화합물 102A-1로부터 실시예 102A를 합성하고(더 빠른 용리) 화합물 012B-1로부터 실시예 102B를 합성하였다(더 느린 용리).Example 102A was synthesized from Compound 102A-1 (more rapid elution) in Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 and compound 102B was synthesized from compound 012B-1 Slow elution).
트랜스Trance -- 메틸 3-옥소-1,5,6,7,8,8a-헥사하이드로옥사졸로[3,4-a]피라진-8-카복실레이트(화합물 102-C)의 제조Preparation of methyl 3-oxo-1,5,6,7,8,8a-hexahydrooxazolo [3,4-a] pyrazine-8-carboxylate (Compound 102-C)
단계 1 : DCM(80 mL) 중 화합물 82-C-1(8.6 g, 23 mmol) 및 피리딘(3.64 g, 46 mmol)의 교반된 용액에 0℃에서 DCM(20 mL) 중 (4-니트로페닐) 카보노클로리데이트(6.95 g, 34.5 mmol)의 용액을 첨가하였다. 이어서, 혼합물을 실온으로 가온하고 약 2 내지 3 시간 동안 교반하였다. 용매를 DCM(100 mL)으로 희석하고, 혼합물을 0.6 N HCl(50 mL), 수성 NaHCO3(50 mL) 및 염수로 순차적으로 세척하였다. 유기 층을 Na2SO4로 건조하고, 여과하고 진공에서 농축하였다. 수득된 조질 생성물을 실리카 컬럼 크로마토그래피로 정제하여 생성물 102-C-1(9.5 g)을 수득하였다. 1H NMR(400 MHz, CDCl3) d ppm 8.30(d, J = 8.8 Hz, 2H), 7.43(t, J = 8.5 Hz, 2H), 5.30-5.09(m, 1H), 4.88-4.71(m, 1H), 4.54-4.23(m, 2H), 4.08-3.93(m, 1H), 3.91-3.77(m, 5H),3.33-2.97(m, 1H), 3.33-2.97(m, 1H), 1.51-1.47(t, 18 H). Step 1 : To a stirred solution of 82-C-1 (8.6 g, 23 mmol) and pyridine (3.64 g, 46 mmol) in DCM (80 mL) at 0 C was added (4-nitrophenyl ) Carbon black chloridate (6.95 g, 34.5 mmol) in dichloromethane was added. The mixture was then warmed to room temperature and stirred for about 2 to 3 hours. The solvent was diluted with DCM (100 mL) and the mixture was washed sequentially with 0.6 N HCl (50 mL), aqueous NaHCO 3 (50 mL) and brine. The organic layer was dried with Na 2 SO 4, filtered and concentrated in vacuo. The crude product obtained was purified by silica column chromatography to give the product 102-C-1 (9.5 g). 1 H NMR (400 MHz, CDCl 3) d ppm 8.30 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 8.5 Hz, 2H), 5.30-5.09 (m, 1H), 4.88-4.71 (m (M, IH), 4.51-4.23 (m, 2H), 4.08-3.93 (m, IH), 3.91-3.77 (m, 5H), 3.33-2.97 -1.47 (t, 18 H).
단계 2: DCM(70 mL) 중 화합물 102-C-1(9.5 g, 17.6 mmol)의 용액에 실온에서 TFA(70 mL)를 첨가하였다. 이어서, 혼합물을 약 3 시간 동안 교반하였다. 용매를 감압하에 제거하여 TFA 염으로서 조질 생성물 102-C-2(10 g 조질)를 수득하고, 이를 추가 정제 없이 다음 단계에서 사용하였다. Step 2: To a solution of compound 102-C-1 (9.5 g, 17.6 mmol) in DCM (70 mL) was added TFA (70 mL) at room temperature. The mixture was then stirred for about 3 hours. The solvent was removed under reduced pressure to give the crude product 102-C-2 (10 g crude) as a TFA salt, which was used in the next step without further purification.
단계 3: DCM(160 mL) 중 화합물 102-C-2(조질, 10 g, 17.6 mmol)의 교반된 용액에 실온에서 DIPEA(28 mL)를 첨가하였다. 이어서, 혼합물을 환류 가열하고 약 4 시간 동안 교반하였다. 조질 생성물을 실리카 컬럼 크로마토그래피로 정제하여 표제 화합물 102-C(2 g)를 수득하였다. MS: 계산치 201(MH+), 측정치 201(MH+). Step 3: DIPEA (28 mL) was added at room temperature to a stirred solution of compound 102-C-2 (crude, 10 g, 17.6 mmol) in DCM (160 mL). The mixture was then heated to reflux and stirred for about 4 hours. The crude product was purified by silica column chromatography to give the title compound 102-C (2 g). MS: Calcd 201 (MH + ), found 201 (MH + ).
실시예 103A 및 103B(분리된 2개의 단일 이성질체)Examples 103A and 103B (two isolated single isomers)
에틸 (4R)-6-[[(8R,8aS)-2-t-부틸-8-(하이드록시메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; 및Ethyl (4R) -6 - [[(8R, 8aS) -2-t-butyl-8- (hydroxymethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ , 5- a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- Rate; And
에틸 (4R)-6-[[(8S,8aR)-2-t-부틸-8-(하이드록시메틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트 Ethyl (4R) -6 - [[(8S, 8aR) -2-t-butyl-8- (hydroxymethyl) -3-oxo-5,6,8,8a-tetrahydro- , 5- a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- Rate
실시예 103A 및 103B의 제조Preparation of Examples 103A and 103B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 트랜스-2-t-부틸-8-(하이드록시메틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 103-C)을 사용하여 실시예 82A-1 및 82B-1과 유사하세 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- carboxylate (Compound 82- - ( 2 -t- butyl-8- (hydroxymethyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5- a] pyrazin- Lt; / RTI > was prepared in analogy to Examples 82A-1 and 82B-1.
연황색 고체로서 실시예 103A(43 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 빠르게 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.95(d, J = 3.0 Hz, 1H), 7.74(d, J = 3.0 Hz, 1H), 7.35-7.26(m, 2H), 7.19-7.11(m, 1H), 6.25(s, 1H), 4.43(d, J = 17.6 Hz, 1H), 4.13-4.01(m, 3H), 3.97-3.84(m, 1H), 3.75(dd, J = 4.0, 12.5 Hz, 1H), 3.69-3.60(m, 2H), 3.58-3.51(m, 1H),3.28(dd, J = 7.2, 8.7 Hz, 1H), 3.01(dt, J = 3.1, 12.4 Hz, 1H), 2.81-2.71(m, 1H), 2.53-2.41(m, 2H), 1.39(s, 9H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 103A (43 mg) was obtained as a light yellow solid (eluted faster on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.95 (d , J = 3.0 Hz, 1H), 7.74 (d, J = 3.0 Hz, 1H), 7.35-7.26 (m, 2H), 7.19-7.11 (m, 1H), 6.25 ( s, 1H), 4.43 (d, J = 17.6 Hz, 1H), 4.13-4.01 (m, 3H), 3.97-3.84 (m, 1H), 3.75 (dd, J = 4.0 J = 7.2, 8.7 Hz, 1H), 3.01 (dt , J = 3.1, 12.4 Hz, 1H), 3.69-3.60 (m, 2H), 3.58-3.51 1H), 2.81-2.71 (m, 1H), 2.53-2.41 (m, 2H), 1.39 (s, 9H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
연황색 고체로서 실시예 103B(25 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 천천히 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.98-7.92(m, 1H), 7.77-7.70(m, 1H), 7.33-7.23(m, 2H), 7.19-7.11(m, 1H), 6.24(s, 1H), 4.53(d, J = 17.8 Hz, 1H), 4.08-3.95(m, 3H), 3.74-3.62(m, 4H), 3.57-3.47(m, 1H), 3.26(dd, J = 7.4, 8.7 Hz, 1H), 3.07-2.99(m, 1H), 2.94(d, J = 11.8 Hz, 1H), 2.61(dt, J = 3.5, 11.8 Hz, 1H), 2.50-2.40(m, 1H), 1.39(s, 9H), 1.16-1.10(m, 3H). MS: 계산치 605(MH+), 측정치 605(MH+).Example 10OB (25 mg) was obtained as a light yellow solid (eluted more slowly on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.98-7.92 (m , 1H), 7.77-7.70 (m, 1H), 7.33-7.23 (m, 2H), 7.19-7.11 (m, 1H), 1H), 3.26 (dd , J = 7.8 Hz, 1H), 6.24 (d , J = 7.4, 8.7 Hz, 1H), 3.07-2.99 (m, 1H), 2.94 (d , J = 11.8 Hz, 1H), 2.61 (dt , J = 3.5, 11.8 Hz, 1H), 2.50-2.40 , 1.39 (s, 9H), 1.16-1. 10 (m, 3H). MS: Calcd. 605 (MH + ), Measurement 605 (MH + ).
트랜스Trance -- 메틸 3-옥소-1,5,6,7,8,8a-헥사하이드로옥사졸로[3,4-a]피라진-8-카복실레이트(화합물 102-C)의 제조Preparation of methyl 3-oxo-1,5,6,7,8,8a-hexahydrooxazolo [3,4-a] pyrazine-8-carboxylate (Compound 102-C)
단계 1: H2O(10 mL) 중 LiOHㆍH2O(1.26 g, 30 mmol)를 실온에서 메탄올(40 mL) 중 화합물 92-C-1(3.55 g, 10 mmol)의 용액에 첨가하였다. 혼합물을 실온에서 5 시간 동안 교반한 후, 메탄올을 감압하에 제거하고 혼합물을 2 N HCl 용액으로 pH 5로 조정하였다. 혼합물을 에틸 아세테이트(50 mL, 3회)로 추출하였다. 합한 유기 상을 건조하고 농축하여 조질 생성물 103-C-1(3.14 g)을 수득하고 이를 추가 정제 없이 다음 단계에서 사용하였다. MS: 계산치 342(MH+), 측정치 342(MH+). Step 1: LiOH.H 2 O (1.26 g, 30 mmol) in H 2 O (10 mL) was added to a solution of 92-C-1 (3.55 g, 10 mmol) in methanol (40 mL) . The mixture was stirred at room temperature for 5 hours, then the methanol was removed under reduced pressure and the mixture was adjusted to pH 5 with 2 N HCl solution. The mixture was extracted with ethyl acetate (50 mL, 3 times). The combined organic phases were dried and concentrated to give crude product 103-C-1 (3.14 g) which was used in the next step without further purification. MS: Calcd. 342 (MH + ), Measurement 342 (MH + ).
단계 2: BH3ㆍTHF(THF 중 1 M, 30 mL)를 실온에서 THF(20 mL) 중 화합물 103-C-1(3 g, 8.8 mmol)의 용액에 첨가하였다. 반응 혼합물을 3 시간 동안 환류한 후, 이를 0℃로 냉각하였다. 메탄올을 이전 반응 혼합물에 천천히 첨가하여 반응 생성물을 급랭하였다. 용매를 제거하고 잔사를 컬럼 크로마토그래피로 정제하여 생성물 103-C-2(2.47 g)를 수득하였다. MS: 계산치 328(MH+), 측정치 328(MH+). Step 2: BH 3 .THF (1 M in THF, 30 mL) was added at room temperature to a solution of 103-C-1 (3 g, 8.8 mmol) in THF (20 mL). The reaction mixture was refluxed for 3 hours and then it was cooled to 0 < 0 > C. Methanol was slowly added to the previous reaction mixture to quench the reaction product. The solvent was removed and the residue was purified by column chromatography to give the product 103-C-2 (2.47 g). MS: Calculated 328 (MH < + & gt ; ), found 328 (MH < + & gt ; ).
단계 3: TFA(2 mL)를 실온에서 CH2Cl2(20 mL) 중 화합물 103-C-2(2 g, 6.1 mmol)의 교반 용액에 첨가하였다. 3 시간 후, LC-MS는 출발 물질이 소비되었음을나타내었다. 용매를 제거하여 조질 생성물 103-C를 수득하고, 이를 추가 정제 없이 다음 단계에서 사용하였다. MS: 계산치 228(MH+), 측정치 228(MH+). Step 3: TFA (2 mL) was added to a stirred solution of 103-C-2 (2 g, 6.1 mmol) in CH 2 Cl 2 (20 mL) at room temperature. After 3 hours, LC-MS indicated that the starting material had been consumed. The solvent was removed to give the crude product 103-C which was used in the next step without further purification. MS: Calcd. 228 (MH + ), found 228 (MH + ).
실시예 104A 및 104B(분리된 2개의 단일 이성질체)Examples 104A and 104B (two isolated single isomers)
에틸 (4R)-6-[[(8aR)-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; 및(4R) -6- [[(8aR) -2-Isopropyl-3-oxo-5,6,8,8a-tetrahydro- 1 H- imidazo [1,5- a] pyrazin- Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-2-yl-l, 4-dihydropyrimidine-5-carboxylate; And
에틸 (4R)-6-[[(8aS)-2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트(4R) -6- [[(8aS) -2-Isopropyl-3-oxo-5,6,8,8a-tetrahydro- IH- imidazo [1,5- a] pyrazin- Methyl] -4- (2-chloro-3-fluoro-phenyl) -2-thiazol-
실시예 104A 및 104B의 제조Preparation of Examples 104A and 104B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 2-이소프로필-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 104-C)을 사용하여 실시예 82A-1 및 82B-1과 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- 1 > and 82B-l (l-tert-butoxycarbonylamino) -isopropyl- l, 5,6,7,8,8a-hexahydroimidazo [ , 2 < / RTI > title compounds were prepared.
연황색 고체로서 실시예 104A(71 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 빠르게 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.3 Hz, 1H), 7.75(d, J = 3.0 Hz, 1H), 7.32-7.24(m, 2H), 7.15(t, J = 8.3 Hz, 1H), 6.24(s, 1H), 4.12-4.01(m, 4H), 3.94-3.85(m, 2H), 3.80(dd, J = 2.0, 13.3 Hz, 1H), 3.51(t, J = 8.9 Hz, 1H), 3.18-3.04(m, 2H), 2.99(dd, J = 2.8, 10.8 Hz, 1H), 2.79-2.67(m, 1H), 2.29(t, J = 10.9 Hz, 1H), 2.25-2.17(m, 1H), 1.20-1.10(m, 9H). MS: 계산치 561(MH+), 측정치 561(MH+).Example 104A (71 mg) was obtained as a light yellow solid (eluted faster on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.3 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.32-7.24 (m, 2H), 7.15 (t J = 8.3 Hz, 1H), 6.24 (s, 1H), 4.12-4.01 (m, 4H), 3.94-3.85 (m, 2H), 3.80 (dd , J = 2.0, 13.3 Hz, 1H) t, J = 8.9 Hz, 1H ), 3.18-3.04 (m, 2H), 2.99 (dd, J = 2.8, 10.8 Hz, 1H), 2.79-2.67 (m, 1H), 2.29 (t, J = 10.9 Hz , ≪ / RTI > 1H), 2.25-2.17 (m, 1H), 1.20-1.10 (m, 9H). MS: Calcd. 561 (MH + ), Measurement 561 (MH + ).
연황색 고체로서 실시예 104B(77 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 천천히 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.1 Hz, 1H), 7.75(d, J = 3.3 Hz, 1H), 7.33-7.23(m, 2H), 7.15(t, J = 8.5 Hz, 1H), 6.24(s, 1H), 4.13-4.00(m, 4H), 3.94-3.83(m, 3H), 3.45(t, J = 8.9 Hz, 1H), 3.22-3.12(m, 1H), 3.00(dd, J = 4.0, 9.3 Hz, 1H), 2.93-2.80(m, 2H), 2.34(dt, J = 3.4, 11.6 Hz, 1H), 2.15(t, J = 10.9 Hz, 1H), 1.18-1.09(m, 9H). MS: 계산치 561(MH+), 측정치 561(MH+).Example 104B (77 mg) was obtained as a light yellow solid (eluted more slowly on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.1 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.33-7.23 (m, 2H), 7.15 (t J = 8.5 Hz, 1H), 6.24 (s, 1H), 4.13-4.00 (m, 4H), 3.94-3.83 (m, 3H), 3.45 (t , J = 8.9 Hz, 1H), 3.22-3.12 m, 1H), 3.00 (dd , J = 4.0, 9.3 Hz, 1H), 2.93-2.80 (m, 2H), 2.34 (dt, J = 3.4, 11.6 Hz, 1H), 2.15 (t, J = 10.9 Hz , ≪ / RTI > 1H), 1.18-1.09 (m, 9H). MS: Calcd. 561 (MH + ), Measurement 561 (MH + ).
2-이소프로필-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 104-C)의 제조Preparation of 2-isopropyl-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 104-C)
t-부틸 2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 104-C-1)(1 mmol)을 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물 104-C를 수득하고, 이를 다음 단계에서 직접 사용하였다.(Compound 104-C-1) (1 - tert - Butyl-2-isopropyl-3-oxo-5,6,8,8a-tetrahydro- mmol) was dissolved in CH 2 Cl 2 (3 mL) and TFA (1 mL) was slowly added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give the crude product 104-C which was used directly in the next step.
t-t- 부틸 2-이소프로필-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 104-C-1)의 제조Preparation of butyl 2-isopropyl-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [l, 5-a] pyrazine-7-carboxylate (Compound 104-
2-아미노에탄올 대신에 이소-프로필 아민을 사용하여 화합물 67-D와 유사하게 화합물 104-C-1을 제조하였다.Compound 104-C-1 was prepared similarly to compound 67-D using iso-propylamine instead of 2-aminoethanol.
실시예 105A 및 105B(분리된 2개의 단일 이성질체)Examples 105A and 105B (two isolated isomers)
(8R,8aS)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산; 및(8R, 8aS) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5- ethoxycarbonyl-2-thiazol- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid; And
(8S,8aR)-7-[[(4R)-4-(2-클로로-3-플루오로-페닐)-5-에톡시카본일-2-티아졸-2-일-1,4-다이하이드로피리미딘-6-일]메틸]-2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-8-카복실산(8S, 8aR) -7 - [[(4R) -4- (2-Chloro-3-fluoro-phenyl) -5-ethoxycarbonyl- Yl] methyl] -2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [ Pyrazine-8-carboxylic acid
실시예 105A 및 105B의 제조Preparation of Examples 105A and 105B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 2-(2,2-다이플루오로에틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 105-C)을 사용하여 실시예 82A-1 및 82B-1과 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- - (2,2-difluoroethyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 105-C) Two title compounds were prepared analogously to Examples 82A-1 and 82B-1.
연황색 고체로서 실시예 105A(22 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 빠르게 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.77(d, J = 3.0 Hz, 1H), 7.34-7.26(m, 2H), 7.19-7.12(m, 1H), 6.25(s, 1H), 6.17-5.83(m, 1H), 4.31(d, J = 17.1 Hz, 1H), 4.08-4.00(m, 2H), 3.96-3.86(m, 2H), 3.80(dd, J = 2.0, 13.6 Hz, 1H), 3.74-3.68(m, 1H), 3.66-3.56(m, 3H), 3.28-3.16(m, 1H), 2.95-2.87(m, 2H), 2.53(dt, J = 3.4, 12.0 Hz, 1H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 627(MH+), 측정치 627(MH+).Example 105A (22 mg) was obtained as a light yellow solid (eluted faster on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.77 (d, J = 3.0 Hz, 1H), 7.34-7.26 (m, 2H), 7.19-7.12 (m, 1H), 6.25 (s, 1H), 6.17-5.83 (m, 1H), 4.31 (d , J = 17.1 Hz, 1H), 4.08-4.00 (m, 2H), 3.96-3.86 ), 3.80 (dd , J = 2.0,13.6 Hz, 1H), 3.74-3.68 (m, 1H), 3.66-3.56 (m, 3H), 3.28-3.16 ), 2.53 (dt , J = 3.4, 12.0 Hz, 1H), 1.13 (t , J = 7.2 Hz, 3H). MS: Calculated 627 (MH < + & gt ; ), found 627 (MH < + & gt ; ).
연황색 고체로서 실시예 105B(22 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 천천히 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.0 Hz, 1H), 7.35-7.27(m, 2H), 7.17(t, J = 8.1 Hz, 1H), 6.21(s, 1H), 6.16-5.83(m, 1H), 4.23(d, J = 16.6 Hz, 1H), 4.06-4.00(m, 2H), 3.98-3.81(m, 3H), 3.72-3.66(m, 1H), 3.65-3.55(m, 3H), 3.29-3.17(m, 2H), 3.04(d, J = 10.3 Hz, 1H), 2.66-2.54(m, 1H), 1.12(t, J = 7.2 Hz, 3H). MS: 계산치 627(MH+), 측정치 627(MH+).Example 10OB (22 mg) was obtained as a light yellow solid (eluted more slowly on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.0 Hz, 1H), 7.35-7.27 (m, 2H), 7.17 (t , J = 8.1 Hz, 1H) , 6.21 (s, 1H), 6.16-5.83 (m, 1H), 4.23 (d, J = 16.6 Hz, 1H), 4.06-4.00 (m, 2H), 3.98-3.81 ( m, 3H), 3.72-3.66 (m , 1H), 3.65-3.55 (m, 3H), 3.29-3.17 (m, 2H), 3.04 (d, J = 10.3 Hz, 1H), 2.66-2.54 (m, 1H), 1.12 (t , J = 7.2 Hz, 3H). MS: Calculated 627 (MH < + & gt ; ), found 627 (MH < + & gt ; ).
2-(2,2-다이플루오로에틸)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 105-C)의 제조Preparation of 2- (2,2-difluoroethyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin-3-one (Compound 105-C)
t-부틸 2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 105-C-1)(1 mmol)를 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물 105-C를 수득하고, 이를 다음 단계에서 직접 사용하였다. t- butyl 2- (2,2-difluoro-ethyl) -3-oxo-tetrahydro--5,6,8,8a- -1H- imidazo [1,5-a] pyrazine-7-carboxylate (compound 105-C-1 ) (1 mmol) was dissolved in CH 2 Cl 2 (3 mL) and TFA (1 mL) was slowly added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was removed in vacuo to give the crude product 105-C which was used directly in the next step.
t-t- 부틸 2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트Butyl 2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine-7- (( 화합물 105-C-1)의 제조Preparation of Compound 105-C-1)
2-아미노에탄올 대신에 2,2-다이플루오로에탄아민을 사용하여 화합물 67-D와 유사하게 화합물 105-C-1을 제조하였다.Compound 105-C-1 was prepared similarly to compound 67-D using 2,2-difluoroethanamine instead of 2-aminoethanol.
실시예 106A 및 106B(분리된 2개의 단일 이성질체)Examples 106A and 106B (two isolated isomers)
에틸 (4R)-6-[[(8aR)-2-(2-하이드록시-2-메틸-프로필)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트; 및Methyl-propyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1, 5-a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol- ; And
에틸 (4R)-6-[[(8aS)-2-(2-하이드록시-2-메틸-프로필)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-일]메틸]-4-(2-클로로-3-플루오로-페닐)-2-티아졸-2-일-1,4-다이하이드로피리미딘-5-카복실레이트Methyl-propyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [l, 5-a] pyrazin-7-yl] methyl] -4- (2-chloro-3-fluoro-phenyl) -2- thiazol-
실시예 106A 및 106B의 제조Preparation of Examples 106A and 106B
트랜스-메틸 2-사이클로프로필-3-옥소-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-8-카복실레이트(화합물 82-C) 대신에 2-(2-하이드록시-2-메틸-프로필)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 106-C)을 사용하여 실시예 82A-1 및 82B-1과 유사하게 2개의 표제 화합물을 제조하였다.Instead of trans - methyl 2-cyclopropyl-3-oxo-1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazine-8- - (2-hydroxy-2-methyl-propyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- The title compound was prepared in analogy to example 82A-1 and 82B-1.
연황색 고체로서 실시예 106A(18 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 빠르게 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.96(d, J = 3.0 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.33-7.24(m, 2H), 7.15(t, J = 8.2 Hz, 1H), 6.25(s, 1H), 4.14-4.01(m, 3H), 3.97-3.88(m, 2H), 3.80(dd, J = 2.0, 13.3 Hz, 1H), 3.75-3.69(m, 1H), 3.36(d, J = 4.3 Hz, 1H), 3.24-3.15(m, 2H), 3.13-3.07(m, 1H), 3.01(dd, J = 2.9, 10.9 Hz, 1H), 2.76(d, J = 11.3 Hz, 1H), 2.36(t, J = 10.9 Hz, 1H), 2.22(dt, J = 3.1, 11.6 Hz, 1H), 1.22(s, 6H), 1.13(t, J = 7.2 Hz, 3H). MS: 계산치 591(MH+), 측정치 591(MH+).Example 106A (18 mg) was obtained as a light yellow solid (eluted more rapidly on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.96 (d , J = 3.0 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.33-7.24 (m, 2H), 7.15 (t J = 8.2 Hz, 1H), 6.25 (s, 1H), 4.14-4.01 (m, 3H), 3.97-3.88 (m, 2H), 3.80 (dd , J = 2.0, 3.69 (m, 1H), 3.36 (d, J = 4.3 Hz, 1H), 3.24-3.15 (m, 2H), 3.13-3.07 (m, 1H), 3.01 (dd, J = 2.9, 10.9 Hz, 1H) , 2.76 (d, J = 11.3 Hz, 1H), 2.36 (t, J = 10.9 Hz, 1H), 2.22 (dt, J = 3.1, 11.6 Hz, 1H), 1.22 (s, 6H), 1.13 (t, J = 7.2 Hz, 3 H). MS: Calculated 591 (MH < + & gt ; ), found 591 (MH < + & gt ; ).
연황색 고체로서 실시예 106B(26 mg)를 수득하였다(30% 이소프로판올(0.05% DEA)/CO2로 용리하는 키랄팩 AD-3 컬럼에서 더 천천히 용리). 1H NMR(400 MHz, 메탄올-d4) d ppm 7.97(d, J = 3.3 Hz, 1H), 7.76(d, J = 3.3 Hz, 1H), 7.34-7.24(m, 2H), 7.16(t, J = 8.2 Hz, 1H), 6.24(s, 1H), 4.13-4.01(m, 3H), 3.96-3.84(m, 3H), 3.66(t, J = 9.2 Hz, 1H), 3.30-3.16(m, 3H), 3.14-3.03(m, 1H), 2.95-2.83(m, 2H), 2.36(dt, J = 3.4, 11.6 Hz, 1H), 2.22(t, J = 10.9 Hz, 1H), 1.21(s, 6H), 1.13(t, J = 7.0 Hz, 3H). MS: 계산치 591(MH+), 측정치 591(MH+).Example 26B (26 mg) was obtained as a light yellow solid (eluted more slowly on a Chiralpak AD-3 column eluting with 30% isopropanol (0.05% DEA) / CO 2 ). 1 H NMR (400 MHz, methanol -d 4) d ppm 7.97 (d , J = 3.3 Hz, 1H), 7.76 (d, J = 3.3 Hz, 1H), 7.34-7.24 (m, 2H), 7.16 (t , J = 8.2 Hz, 1H) , 6.24 (s, 1H), 4.13-4.01 (m, 3H), 3.96-3.84 (m, 3H), 3.66 (t, J = 9.2 Hz, 1H), 3.30-3.16 ( m, 3H), 3.14-3.03 (m , 1H), 2.95-2.83 (m, 2H), 2.36 (dt, J = 3.4, 11.6 Hz, 1H), 2.22 (t, J = 10.9 Hz, 1H), 1.21 (s, 6H), 1.13 (t , J = 7.0 Hz, 3H). MS: Calculated 591 (MH < + & gt ; ), found 591 (MH < + & gt ; ).
2-(2-하이드록시-2-메틸-프로필)-1,5,6,7,8,8a-헥사하이드로이미다조[1,5-a]피라진-3-온(화합물 106-C)의 제조A solution of 2- (2-hydroxy-2-methyl-propyl) -1,5,6,7,8,8a-hexahydroimidazo [1,5-a] pyrazin- Produce
t-부틸 2-(2-하이드록시-2-메틸-프로필)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 106-C-1)(1 mmol)를 CH2Cl2(3 mL)에 용해한 후 0℃에서 TFA(1 mL)를 천천히 첨가하였다. 반응 혼합물을 실온에서 1 시간 동안 교반한 후, 용매를 진공에서 제거하여 조질 생성물 106-C를 수득하고, 이를 다음 단계에서 직접 사용하였다. t- butyl 2- (2-hydroxy-2-methyl-propyl) -3-oxo-tetrahydro--5,6,8,8a- -1H- imidazo [1,5-a] pyrazine-7-carboxylate (Compound 106-C-1) (1 mmol) was dissolved in CH 2 Cl 2 (3 mL) and TFA (1 mL) was slowly added at 0 ° C. After the reaction mixture was stirred at room temperature for 1 hour, the solvent was removed in vacuo to give crude product 106-C which was used directly in the next step.
t-t- 부틸 2-(2,2-다이플루오로에틸)-3-옥소-5,6,8,8a-테트라하이드로-1H-이미다조[1,5-a]피라진-7-카복실레이트(화합물 106-C-1)의 제조Butyl 2- (2,2-difluoroethyl) -3-oxo-5,6,8,8a-tetrahydro-1H-imidazo [1,5- a] pyrazine- 7- carboxylate (Compound 106- C-1)
2-아미노에탄올 대신에 1-아미노-2-메틸-프로판-2-올을 사용하여 화합물 67-D와 유사하게 화합물 105-C-1을 제조하였다.Compound 105-C-1 was prepared similarly to compound 67-D using 1-amino-2-methyl-propan-2-ol instead of 2-aminoethanol.
실시예 107: HBV 억제 분석Example 107: HBV inhibition assay
세포 및 배양 조건Cell and culture conditions
HepG2.2.15 및 HepDE19는 HBV 게놈을 함유하는 안정하게 형질감염된 세포주이다. 두 세포주는 각각 문헌[MA Selles et al., Proc. Natl. Acad. Sci. USA 1987, 84, 1005-1009] 및 문헌[H Guo et al., Journal of Virology 2007, 81, 12472-12484]에 기재된 공개된 절차에 의해 간모세포종 세포주 Hep G2(아메리칸 타입 컬쳐 콜렉션, ATCC(등록상표) HB-8065(상표))로부터 유도된다. 두 세포주를 10% 소 태아 혈청, 100 U/mL 페니실린, 100 μg/mL 스트렙토마이신 및 0.5 mg/mL의 G418이 보충된 듈베코 개질된 이글 배지(DMEM)-F12 배지에서 유지하였다.HepG2.2.15 and HepDE19 are stably transfected cell lines containing the HBV genome. Both cell lines are described by MA Selles et al., Proc. Natl. Acad. Sci. USA Hepatocellular carcinoma cell line Hep G2 (American Type Culture Collection, ATCC (registered trademark)) by the published procedure described in US Provisional Patent Application Serial No. 10 / Trademark) HB-8065 (trademark). Two cell lines were maintained in Dulbecco's modified Eagle's medium (DMEM) -F12 medium supplemented with 10% fetal bovine serum, 100 U / mL penicillin, 100 ug / mL streptomycin and 0.5 mg / mL G418.
HepG2.2.15 세포는 본질적으로 HBV 복제 및 바이러스 입자의 생성을 지지하는 반면, HepDE19 세포는 테트라사이클린에 의해 유도가능하다. 배양 배지 중에 1 μg/mL 테트라사이클린을 첨가하면 HepDE19 세포에서 HBV 복제를 억제하는 반면, 테트라사이클린-무함유 배지로 전환하면 이 과정을 재시작한다.HepG2.2.15 cells essentially support HBV replication and viral particle production, whereas HepDE19 cells are inducible by tetracycline. Addition of 1 μg / mL tetracycline in the culture medium inhibits HBV replication in HepDE19 cells, while switching to tetracycline-free medium restarts this process.
시험관내 항-HBV 활성In vitro anti-HBV activity
HepG2.2.15 세포를 96-웰 플레이트에 시딩하고(웰당 100 μL 배지 중 3 x 104 세포) 밤새 37℃에서 항온처리하였다. 시험 화합물을 DMSO 중에 일련의 반-로그로 희석한 후, 배양 배지 중에 100 배 희석하였다. 희석된 화합물(100 μL)을 플레이트에 첨가하여 모든 웰에서 DMSO의 최종 농도는 0.5%에 도달하였다. 화합물 처리 5 일 후, 추가 분석을 위해 배양 상청액을 수집하였다.HepG2.2.15 cells were seeded into 96-well plates (3 x 10 4 cells in 100 μL medium per well) and incubated overnight at 37 ° C. The test compound was diluted with a series of semi-log in DMSO and then diluted 100-fold in the culture medium. The diluted compound (100 [mu] L) was added to the plate and the final concentration of DMSO in all wells reached 0.5%. After 5 days of compound treatment, the culture supernatant was collected for further analysis.
세포외 HBV DNA의 정량 PCR 검출을 위해, 배양 상청액(100 μL)을 수집하고 바이러스 DNA 추출을 위해 MagNA 퓨어 96 핵산 정제 시스템(로슈 어플라이드 사이언스(Roche Applied Science))에서 처리하였다. 추출된 샘플을 qPCR에 의해 HBV DNA 정량에 이용하였다. HBV 복제가 50% 억제되는 효과적인 화합물 농도(EC50)를 표 1에 나타낸 바와 같이 측정하였다.For quantitative PCR detection of extracellular HBV DNA, the culture supernatant (100 μL) was collected and processed in a MagNA Pure 96 nucleic acid purification system (Roche Applied Science) for viral DNA extraction. The extracted samples were used for quantification of HBV DNA by qPCR. Effective compound concentrations (EC 50 ) with 50% inhibition of HBV replication were measured as shown in Table 1. [
본 발명의 화합물을 본원에 기재된 바와 같이 HBV 활성 및 활성화를 억제하는 이의 능력에 대하여 시험하였다. 실시예를 본원에 기재된 바와 같이 상기 분석에서 시험하고, HepG2.2.15 분석시 EC50이 0.2 μM 미만임이 밝혀졌다. 본 발명의 화학식 I의 특정한 화합물 또는 다른 화합물은 HepG2.2.15 분석시 EC50이 0.02 μM 미만임이 밝혀졌다.Compounds of the present invention were tested for their ability to inhibit HBV activity and activation as described herein. The examples were tested in this assay as described herein and the Hep 50.2.15 assay was found to have an EC 50 of less than 0.2 μM. Certain compounds of formula I or other compounds of the invention have been found to have an EC 50 of less than 0.02 μM when analyzed by HepG2.2.15.
[표 1][Table 1]
HepG2.2.15 세포에서 특정한 화합물의 항-HBV 활성 데이타Anti-HBV activity data of a specific compound in HepG2.2.15 cells
세포독성 및 선택 지수Cytotoxicity and selectivity index
HepDE19 세포를 96-웰 플레이트에 시딩하고(웰당 5 x 103 세포) EC50 측정을 위해 화합물로 처리하였다. 처리 5 일 후, CCK-8 시약(20 μL)을 첨가하여 세포 생존력을 측정하였다. 37℃에서 2 시간 항온처리 후, 450 nm 및 630 nm의 파장에서의 흡광도(OD450 및 OD630)를 플레이트 판독기로 기록하였다. 각각의 화합물의 숙주 세포의 50% 사멸을 야기하는 농도(CC50)를 측정하였다.HepDE 19 cells were seeded into 96-well plates (5 x 10 3 cells per well) and treated with compounds for EC 50 determinations. After 5 days of treatment, CCK-8 reagent (20 [mu] L) was added to measure cell viability. After incubation at 37 ° C for 2 hours, the absorbance at 450 nm and 630 nm (OD 450 and OD 630 ) was recorded with a plate reader. The concentration (CC 50 ) causing 50% kill of the host cells of each compound was determined.
세포 사멸을 유도하는 것과 비교하여 바이러스 복제를 억제하는 화합물의 상대적인 효과를 선택 지수(CC50 값/EC50 값)로서 정의하였다. CC50 및 EC50 데이타에 기초하여, 선택 지수를 측정하였다.The relative effect of compounds inhibiting viral replication as compared to inducing apoptosis was defined as the selectivity index (CC 50 value / EC 50 value). The selectivity index was measured based on CC 50 and EC 50 data.
CC50 및 상응하는 선택 지수의 결과를 하기 표 2에 나타내었다.The results of CC 50 and corresponding selectivities are shown in Table 2 below.
[표 2][Table 2]
특정한 화합물의 CC50 및 선택 지수The CC 50 and selectivity index of a particular compound
실시예 108: 인간 마이크로솜 대사 안정성Example 108: Human microsomal metabolic stability
인간 마이크로솜(비디 젠테스트(BD Gentest))을 100 mM 포스페이트 완충제(pH 7.4) 중에서 시험 화합물로 10 분 동안 37℃에서 예비항온처리하였다. NADPH 또는 NADPH 재생 시스템을 첨가함으로써 반응을 개시하여 최종 항온처리 용량(400 μL)을 수득하였다. NADPH 시스템의 경우, 최종 항온처리는 100 mM 포스페이트 완충제(pH 7.4) 중에 1 μM 시험 화합물, 0.5 mg/mL 간 마이크로솜 단백질, 1 mM NADPH를 함유하였다. NADPH 재생 시스템의 경우, 최종 항온처리는 100 mM 포스페이트 완충제(pH 7.4) 중에 1 μM 시험 화합물, 0.5 mg/mL 간 마이크로솜 단백질, 3 mM 글루코스 6-포스페이트, 1 mM NADP, 3 mM MgCl2 및 0.05 mg/mL 글루코스 6-포스페이트 데하이드로게나아제를 함유하였다. 37℃에서 0, 3, 6, 9, 15 및 30 분의 항온처리 시간 후, 각각의 시점으로부터 1개의 샘플을 수득하고, 각각의 샘플(50 μL)을 제거하고 메탄올 용액(150 μL)으로 옮기고, 이를 4℃에서 유지하고 내부 표준으로서 2 μM 톨부타미드를 함유하였다. 침전 및 원심분리 후, 샘플 중에 남아있는 화합물의 양을 LC-MS/MS로 측정하였다. 0 및 30 분에서 NADPH가 없거나 NADPH 재생 시스템이 없는 대조군을 또한 제조하고 분석하였다.Human microsomes (BD Gentest) were pre-incubated with test compounds in 100 mM phosphate buffer (pH 7.4) for 10 min at 37 [deg.] C. The reaction was initiated by addition of NADPH or NADPH regeneration system to give a final thermostatted volume (400 μL). For the NADPH system, final incubation contained 1 μM test compound, 0.5 mg / mL hepatic microsomal protein, 1 mM NADPH in 100 mM phosphate buffer (pH 7.4). For the NADPH regeneration system, the final incubation was performed in the presence of 1 μM test compound, 0.5 mg / mL liver microsomal protein, 3 mM glucose 6-phosphate, 1 mM NADP, 3 mM MgCl 2 and 0.05 mg / mL glucose 6-phosphate dehydrogenase. After incubation times of 0, 3, 6, 9, 15 and 30 minutes at 37 占 폚, one sample was obtained from each time point and each sample (50 占)) was removed and transferred to a methanol solution (150 占 고) , Which was maintained at 4 [deg.] C and contained 2 [mu] M tolbutamide as an internal standard. After precipitation and centrifugation, the amount of the compound remaining in the sample was measured by LC-MS / MS. Controls without or with NADPH regeneration system at 0 and 30 min were also prepared and analyzed.
인간 마이크로솜에서의 대사 안정성 연구 결과를 하기 표 3에 나타내었다.The results of metabolic stability studies in human microsomes are shown in Table 3 below.
[표 3][Table 3]
인간 마이크로솜에서의 대사 안정성Metabolic stability in human microsomes
실시예 109: Lysa 용해도Example 109: Lysa solubility
10 mM DMSO 스톡 용액으로부터 샘플을 이중으로 제조하였다. 원심 진공 증발기로 DMSO를 증발시킨 후, 잔사를 0.05 M 포스페이트 완충제(pH 6.5)에 용해하고, 1 시간 동안 교반하고, 2 시간 동안 진탕하였다. 하룻밤이 지난 후, 용액을 마이크로역가 필터 플레이트를 사용하여 여과하였다. 이어서, 여액 및 이의 1/10 희석액을 직접 UV 측정에 의해 또는 HPLC-UV에 의해 분석하였다. 또한, 10 mM 스톡 용액으로부터 4-점 보정 곡선을 제조하고 화합물의 용해도 측정을 위해 사용하였다. 결과를 μg/mL 단위로 나타내었다. 증발 후 용액 중에서 측정된 샘플의 %를 계산된 최대 샘플 양으로 나눈 %가 80%를 초과하는 경우, 용해도는 이 값보다 큰 것으로 기록하였다.Duplicate samples were prepared from 10 mM DMSO stock solutions. After evaporation of the DMSO with a centrifugal vacuum evaporator, the residue was dissolved in 0.05 M phosphate buffer (pH 6.5), stirred for 1 hour and shaken for 2 hours. After one night, the solution was filtered using a microtiter filter plate. The filtrate and its 1/10 dilution were then analyzed by direct UV measurement or by HPLC-UV. A 4-point calibration curve was also prepared from the 10 mM stock solution and used for solubility measurement of the compound. The results were expressed in μg / mL. If the% of the sample measured in solution after evaporation divided by the calculated maximum sample amount exceeds 80%, the solubility is recorded as being greater than this value.
Lysa 결과를 하기 표 4에 나타내었다.The results of Lysa are shown in Table 4 below.
[표 4][Table 4]
특정한 화합물의 용해도 데이타The solubility data of a particular compound
실시예 110: 시토크롬 P450(Cyp450) 유도 스크리닝 분석-mRNA 유도Example 110: Cytochrome P450 (Cyp450) -induced screening assay-mRNA induction
재료material
세포 배양Cell culture
저온보존된 인간 간세포(라이프 테크놀로지즈(Life Technologies), 미국 칼스배드 소재)를 해동시키고 콜라겐 I 코팅된 96-웰 플레이트에서 52,000 세포/웰의 밀도로 배양하였다. 부착 후, 배지를 교환하고, 세포를 간세포 유지 배지(HMM; 론자(Lonza), 스위스 소재) 중에서 밤새 예비-배양하였다.Cold-preserved human hepatocytes (Life Technologies, Carlsbad, USA) were thawed and cultured in collagen I-coated 96-well plates at a density of 52,000 cells / well. After attachment, the medium was changed and the cells were pre-incubated overnight in hepatocyte maintenance medium (HMM; Lonza, Switzerland).
시험 화합물을 겐타마이신 및 일정한 0.1% DMSO를 함유하는 HMM 배양 배지 중에서 지시된 농도(10 μM 이하)로 다음날 아침 세포에 투여하였다. 유사하게, 양성 유도제 화합물인 오메프라졸(인간 CYP1A2의 원형 유도제; 최종 농도: 1 및 10 μM), 페노바르비탈(인간 CYP2B6의 원형 유도제; 최종 농도: 100 및 1000 μM) 및 리팜피신(인간 CYP3A4의 원형 유도제; 최종 농도: 1 및 10 μM)의 희석을 겐타마이신을 함유하는 HMM 중에서 1000배 DMSO 스톡 용액으로부터 제조하였다. 이어서, 배지 교환을 수행하고, 세포를 24 시간 동안 각각 시험 화합물, 양성 유도제 화합물, 또는 비히클(0.1% DMSO)에 노출시켰다.Test compounds were administered to the cells the following morning at the indicated concentrations (less than 10 [mu] M) in HMM culture medium containing gentamicin and constant 0.1% DMSO. Similarly, the positive inducer compounds omeprazole (prototype of human CYP1A2 prototype; final concentrations: 1 and 10 μM), phenobarbital (prototype inducer of human CYP2B6; final concentrations 100 and 1000 μM) and rifampicin (prototype inducer of human CYP3A4; Concentration: 1 and 10 [mu] M) was prepared from 1000-fold DMSO stock solution in HMM containing gentamycin. Subsequently, medium exchange was performed and the cells were exposed to the test compound, positive inducer compound, or vehicle (0.1% DMSO), respectively, for 24 hours.
화합물 노출 기간이 끝나면, 배지를 제거하고, 세포를 100 μL/웰 MagNA 퓨어 LC RNA 단리 조직 용해 완충제(로슈 디아그노스틱스 아게(Roche Diagnostics AG), 스위스 로트크로이츠 소재)를 사용하여 용해하였다. 이어서, 플레이트를 밀봉하고, 추가 후처리시까지 -80℃에서 냉동시켰다.At the end of the compound exposure period, the media was removed and the cells were lysed using 100 μL / well MagNA pure LC RNA isolation tissue lysis buffer (Roche Diagnostics AG, Rothschild, Switzerland). The plate was then sealed and frozen at -80 DEG C until further post treatment.
mRNA 단리, 프로세싱 및 qRT-PCRmRNA isolation, processing and qRT-PCR
PBS로 1:1 희석된 해동된 샘플로부터 MagNA 퓨어 96 시스템(로슈 디아그노스틱스 아게, 스위스 로트크로이츠 소재) 및 각각의 세포의 RNA 대용량 키트(로슈 디아그노스틱스 아게, 스위스 로트크로이츠 소재)를 사용하여 mRNA 단리를 수행하였다. 세포 용해 용량 및 100 μL의 용리 용량을 사용하였다. 이어서, 생성된 mRNA 현탁액(20 μL)을, 전사체(20 μL) 또는 제 1 가닥 cDNA 합성 키트(로슈 프라임 서플라이(Roche prime Supply), 독일 만하임 소재)를 사용하는 역 전사에 사용하였다. 생성된 cDNA를, qRT-PCR에 사용하기 전에, H2O(40 μL)로 희석하였다. qRT-PCR을, 정방향 프라이머 및 역방향 프라이머, 상응하는 UPL(모두 마이크로신쓰(Microsynth)로부터 구입가능, 스위스 발가흐 소재) 및 택맨 패스트 어드밴스드 마스터 믹스(Taqman Fast advanced master mix; 어플라이드 바이오시스템스(Applied Biosystems))를 사용하여 ABI 7900 기계(어플라이드 바이오시스템스)에서 수행하였다.The thawed samples were diluted 1: 1 in PBS using the MagNA Pure 96 system (Roche Diagnostics, Rottweil, Switzerland) and the RNA bulk kit of each cell (Roche Diagnostics AG, Rothschild, Switzerland) mRNA isolation was performed. Cell lysis volume and 100 μL elution volume were used. The resulting mRNA suspension (20 μL) was then used for reverse transcription using a transcript (20 μL) or a first strand cDNA synthesis kit (Roche prime Supply, Mannheim, Germany). The resulting cDNA was diluted with H 2 O (40 μL) before use in qRT-PCR. qRT-PCR was performed using a forward primer and reverse primer, the corresponding UPL (all available from Microsynth, Vogel, Switzerland) and a Taqman Fast advanced master mix (Applied Biosystems) ) On an ABI 7900 machine (Applied Biosystems).
계산Calculation
각각의 P450에 대한 qRT-PCR Ct-값을 동일한 샘플의 RN18S1(마이크로신쓰, 스위스 발가흐 소재)의 Ct-값과 관련하여 표현하였다. 그렇게 하여, 각각의 Δct-값을 계산하였다. 비히클 대조군 샘플에 대한 모든 Δct-값의 평균을 사용하여, 각각의 샘플에 대한 ΔΔct-값을 계산하였다(ΔΔct-값(샘플) = Δct-값(샘플) - 모든 비히클 대조군의 Δct-값의 평균). 각각의 샘플의 배수 유도를 2^(-ΔΔct)로 계산하였다. 이어서, 개별적인 배수 유도 값을 치료 조건당 평균내었다(통상적으로 n=3 생물학적 복제).The qRT-PCR Ct-values for each P450 were expressed relative to the Ct-values of the same sample of RN18S1 (Microsyn, Switzerland, Valgat). Thus, each? T-value was calculated. The ΔΔct-value for each sample was calculated using the average of all Δct-values for the vehicle control sample (ΔΔct-value (sample) = Δct-value (sample) - average of Δct-values of all vehicle controls ). The multiple induction of each sample was calculated as 2 ^ (- ΔΔct). Individual drainage values were then averaged per treatment condition (typically n = 3 biological replicates).
이어서, 각각의 양성 유도제 화합물 조건(CYP1A2에 대하여 10 μM 오메프라졸; CYP2B6에 대하여 1000 μM 페노바르비탈; CYP3A4에 대하여 10 μM 리팜피신)에 대한 상대적인 유도 값을 다음과 같이 배수 유도 값으로부터 계산하였다:The relative induction values for each positive inducer compound condition (10 [mu] M omeprazole for CYP1A2, 1000 [mu] M phenobarbital for CYP2B6 and 10 [mu] M rifampicin for CYP3A4) were then calculated from the multiple derived values as follows:
상대적인 유도(%) = 100 x (T-V)/(P-V) Relative Induction (%) = 100 x (T-V) / (P-V)
상기 식에서,In this formula,
T는 시험 화합물 조건의 배수 유도이고;T is a multiple induction of test compound conditions;
P는 양성 유도제 화합물의 배수 유도이고;P is a multiple induction of the positive inducer compound;
V는 비히클 대조군의 배수 유도이다.V is the drainage induction of the vehicle control.
CYP3A4 유도의 결과를 하기 표 5에 나타내었다.The results of CYP3A4 induction are shown in Table 5 below.
[표 5][Table 5]
10 μM 리팜피신에 대한 특정한 화합물의 상대적인 유도 값Relative Induced Values of Specific Compounds for 10 μM Rifampicin
Claims (3)
[화학식 IAA]
상기 식에서,
R1은 클로로 또는 메틸이고;
R2는 수소 또는 플루오로이고;
R3은 수소 또는 플루오로이고;
R4는 메틸 또는 에틸이고;
R5는 수소 또는 카복시이고;
R6은 수소이고;
R7은 메틸, 이소프로필, t-부틸, 사이클로프로필, 카복시(젬다이메틸)에틸, 카복시(젬다이메틸)프로필, 카복시사이클로프로필메틸, 카복시사이클로부틸메틸 또는 카복시페닐이다.A compound of the formula IAA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
(IAA)
In this formula,
R 1 is chloro or methyl;
R 2 is hydrogen or fluoro;
R < 3 > is hydrogen or fluoro;
R < 4 > is methyl or ethyl;
R < 5 > is hydrogen or carboxy;
R < 6 > is hydrogen;
R 7 is methyl, isopropyl, t-butyl, cyclopropyl, carboxy (gemidemethyl) ethyl, carboxy (gemidemethyl) propyl, carboxycyclopropylmethyl, carboxycyclobutylmethyl or carboxyphenyl.
[화학식 IAA]
상기 식에서,
R1은 할로겐 또는 C1- 6알킬이고;
R2는 수소 또는 할로겐이고;
R3은 수소 또는 할로겐이고;
R4는 C1- 6알킬이고;
R5는 수소 또는 카복시이고;
R6은 수소이고;
R7은 C1- 6알킬, 할로C1 - 6알킬, C3- 7사이클로알킬, -CmH2m-COOH, -CmH2m-C3- 7사이클로알킬-COOH 또는 카복시페닐이고;
m은 1 내지 6이다.A compound of the formula IAA, or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof,
(IAA)
In this formula,
R 1 is halogen or C 1- 6 alkyl;
R < 2 > is hydrogen or halogen;
R < 3 > is hydrogen or halogen;
R 4 is C 1- 6 alkyl;
R < 5 > is hydrogen or carboxy;
R < 6 > is hydrogen;
R 7 is C 1- 6 alkyl, halo C 1 - 6 alkyl, C 3- 7 cycloalkyl, -C m H 2m -COOH, -C m H 2m -C 3- 7 cycloalkyl, -COOH or a carboxy-phenyl;
m is 1 to 6;
[화학식 IAB]
상기 식에서,
R1은 할로겐 또는 C1- 6알킬이고;
R2는 수소 또는 할로겐이고;
R3은 수소 또는 할로겐이고;
R4는 C1- 6알킬이고;
R5는 수소이고;
R6은 수소이고;
R8은 -CmH2m-, C3- 7사이클로알킬-CmH2m- 또는 페닐이고;
m은 1 내지 6이다.Claims 1. A compound of formula (IAB), or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof:
(IAB)
In this formula,
R 1 is halogen or C 1- 6 alkyl;
R < 2 > is hydrogen or halogen;
R < 3 > is hydrogen or halogen;
R 4 is C 1- 6 alkyl;
R < 5 > is hydrogen;
R < 6 > is hydrogen;
R 8 is -C m H 2m - or a phenyl -, C 3- 7 cycloalkyl, -C m H 2m;
m is 1 to 6;
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Families Citing this family (187)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ME01924B (en) | 2010-07-22 | 2015-05-20 | Gilead Sciences Inc | Methods and compounds for treating Paramyxoviridae virus infections |
SG11201402660YA (en) | 2011-12-21 | 2014-10-30 | Novira Therapeutics Inc | Hepatitis b antiviral agents |
WO2014033170A1 (en) | 2012-08-28 | 2014-03-06 | Janssen R&D Ireland | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis b |
ES2628953T3 (en) | 2013-02-28 | 2017-08-04 | Janssen Sciences Ireland Uc | Sulfamoylarylamides and their use as medicines for the treatment of hepatitis B |
AU2014247138B2 (en) | 2013-04-03 | 2018-06-28 | Janssen Sciences Ireland Uc | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
TW201512193A (en) * | 2013-05-17 | 2015-04-01 | Hoffmann La Roche | Novel 6-bridged heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection |
JO3603B1 (en) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
EA035500B1 (en) | 2013-05-17 | 2020-06-25 | Янссен Сайенсиз Айрлэнд Юси | Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
EA035926B1 (en) | 2013-07-25 | 2020-09-01 | Янссен Сайенсиз Айрлэнд Юси | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
JP6452119B2 (en) | 2013-10-23 | 2019-01-16 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | Carboxamide derivatives and their use as pharmaceuticals for the treatment of hepatitis B |
SG11201601813UA (en) | 2013-11-27 | 2016-04-28 | Sunshine Lake Pharma Co Ltd | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
MX2016009449A (en) | 2014-02-05 | 2016-10-13 | Novira Therapeutics Inc | Combination therapy for treatment of hbv infections. |
UY35980A (en) | 2014-02-06 | 2015-08-31 | Janssen Sciences Ireland Uc | DERIVATIVES OF SULFAMOILPIRROLAMIDA AS INHIBITORS OF HBV AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
CR20160337A (en) * | 2014-03-07 | 2016-09-20 | Hoffmann La Roche | NEW HETEROARILDIHYDROPIRIMIDINES 6-FUSIONATED FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION |
AU2015236982B2 (en) | 2014-03-28 | 2017-12-14 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
BR112016028000B1 (en) * | 2014-05-30 | 2022-05-17 | Qilu Pharmaceutical Co., Ltd | Loop derivative of dihydropyrimide as an hbv inhibitor |
TWI740546B (en) | 2014-10-29 | 2021-09-21 | 美商基利科學股份有限公司 | Methods for the preparation of ribosides |
CN105859708B (en) | 2015-02-07 | 2020-01-21 | 广东东阳光药业有限公司 | Salts of dihydropyrimidine derivatives and their use in medicine |
ES2798598T3 (en) * | 2015-03-16 | 2020-12-11 | Hoffmann La Roche | Combination therapy with a TLR7 agonist and an HBV capsid assembly inhibitor |
US10442788B2 (en) | 2015-04-01 | 2019-10-15 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
WO2016183266A1 (en) | 2015-05-13 | 2016-11-17 | Enanta Pharmaceuticals, Inc. | Ehpatitis b antiviral agents |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10179131B2 (en) | 2015-07-13 | 2019-01-15 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US10301255B2 (en) | 2015-07-22 | 2019-05-28 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
EP3349758B1 (en) | 2015-09-16 | 2022-04-06 | Gilead Sciences, Inc. | Methods for treating arenaviridae virus infections |
EP3350200A4 (en) | 2015-09-18 | 2019-03-27 | Wake Forest University Health Services | Angiotensin (1-7) analogs and methods relating thereto |
WO2017064156A1 (en) | 2015-10-16 | 2017-04-20 | F. Hoffmann-La Roche Ag | Novel 6-fused and 2-heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
WO2017076791A1 (en) * | 2015-11-03 | 2017-05-11 | F. Hoffmann-La Roche Ag | Combination therapy of an hbv capsid assembly inhibitor and an interferon |
CA2914601A1 (en) * | 2015-12-11 | 2017-06-11 | Wake Forest University Health Sciences | Angiotensin-(1-7) analogs and methods relating thereto |
WO2017108630A1 (en) * | 2015-12-21 | 2017-06-29 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and an hbv capsid assembly inhibitor |
US10280175B2 (en) | 2016-02-02 | 2019-05-07 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
KR20180110131A (en) | 2016-02-19 | 2018-10-08 | 노파르티스 아게 | Tetracyclic pyridone compounds as antiviral agents |
AR107633A1 (en) * | 2016-02-19 | 2018-05-16 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF ACID 4-PHENYL-5-ALCOXICARBONIL-2-TIAZOL-2-IL-1,4-DIHYDROPIRIMIDIN-6-IL- [METHYL] -3-OXO-5,6,8,8A-TETRAHIDRO- 1H-IMIDAZO [1,5A] PIRAZIN-2-IL-CARBOXYL |
JP6904970B2 (en) | 2016-03-07 | 2021-07-21 | エナンタ ファーマシューティカルズ インコーポレイテッド | Hepatitis B antiviral agent |
SG10202011827YA (en) | 2016-04-15 | 2021-01-28 | Novira Therapeutics Inc | Combinations and methods comprising a capsid assembly inhibitor |
DE202016102339U1 (en) * | 2016-05-03 | 2016-06-22 | Freund Maschinenfabrik Gmbh & Co. Kg | Sliding block for a saw blade in a band saw machine |
JP6957518B2 (en) * | 2016-05-20 | 2021-11-02 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | A novel pyrazine compound with oxygen, sulfur and nitrogen linkers for the treatment of infectious diseases |
WO2017214395A1 (en) | 2016-06-10 | 2017-12-14 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
WO2017216686A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | 8,9-fused 2-oxo-6,7-dihydropyrido-isoquinoline compounds as antivirals |
WO2017216685A1 (en) | 2016-06-16 | 2017-12-21 | Novartis Ag | Pentacyclic pyridone compounds as antivirals |
CN109715624B (en) * | 2016-07-29 | 2022-08-16 | 广州麓鹏制药有限公司 | Novel therapeutic agents for the treatment of HBV infection |
CN109689059A (en) * | 2016-08-24 | 2019-04-26 | 豪夫迈·罗氏有限公司 | The combination treatment of HBV Mouth Disease Virus Proteins inhibitor and nucleosides or nucleotide analog |
WO2018045150A1 (en) | 2016-09-02 | 2018-03-08 | Gilead Sciences, Inc. | 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators |
EP3507276B1 (en) | 2016-09-02 | 2021-11-03 | Gilead Sciences, Inc. | Toll like receptor modulator compounds |
TW201811788A (en) | 2016-09-09 | 2018-04-01 | 瑞士商諾華公司 | Polycyclic pyridone compounds as antivirals |
KR102497701B1 (en) * | 2016-09-13 | 2023-02-09 | 에프. 호프만-라 로슈 아게 | Combination therapy of a TLR7 agonist and an HBV capsid assembly inhibitor |
KR20230010826A (en) | 2016-10-14 | 2023-01-19 | 프리시젼 바이오사이언시스 인코포레이티드 | Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome |
WO2018073753A1 (en) | 2016-10-18 | 2018-04-26 | Novartis Ag | Fused tetracyclic pyridone compounds as antivirals |
CN116751200A (en) | 2016-11-07 | 2023-09-15 | 爱彼特生物制药公司 | Tricyclic compounds containing substituted pyridones and methods of using the same |
JP7139568B2 (en) | 2016-11-18 | 2022-09-21 | シチュアン ケルン-バイオテック バイオファーマシューティカル カンパニー リミテッド | Dihydropyrimidine compound and its preparation method and use |
US11166954B2 (en) | 2016-11-18 | 2021-11-09 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Dihydropyrimidine compound and preparation method and use thereof |
CN108341810B (en) * | 2017-01-23 | 2022-01-18 | 上海长森药业有限公司 | Episulfide urea compound and application thereof |
TWI714820B (en) | 2017-01-31 | 2021-01-01 | 美商基利科學股份有限公司 | Crystalline forms of tenofovir alafenamide |
WO2018169946A1 (en) * | 2017-03-14 | 2018-09-20 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
EP3601216B1 (en) | 2017-03-21 | 2023-10-25 | Arbutus Biopharma Corporation | Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same for the treatment of hepatitis b virus infection |
JOP20180040A1 (en) | 2017-04-20 | 2019-01-30 | Gilead Sciences Inc | Pd-1/pd-l1 inhibitors |
AR111419A1 (en) | 2017-04-27 | 2019-07-10 | Novartis Ag | INDAZOL PIRIDONA FUSIONED COMPOUNDS AS ANTIVIRALS |
CN110636884B (en) | 2017-05-01 | 2022-10-04 | 吉利德科学公司 | Novel crystalline forms |
KR102665544B1 (en) * | 2017-06-26 | 2024-05-14 | 선샤인 레이크 파르마 컴퍼니 리미티드 | Dihydropyrimidine compounds and their use in medicine |
KR20200020887A (en) | 2017-06-27 | 2020-02-26 | 얀센 파마슈티카 엔.브이. | Heteroaryldihydropyrimidine Derivatives and Methods of Treating Hepatitis B Infection |
US10675296B2 (en) | 2017-07-11 | 2020-06-09 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
CA3073986A1 (en) | 2017-08-28 | 2019-03-07 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
CA3079557A1 (en) * | 2017-10-18 | 2019-04-25 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and uses thereof in medicine |
US11267825B2 (en) | 2017-11-02 | 2022-03-08 | Aicuris Gmbh & Co. Kg | Highly active amino-thiazole substituted indole-2-carboxamides active against the hepatitis B virus (HBV) |
AU2018361365C1 (en) | 2017-11-02 | 2021-08-05 | Aicuris Gmbh & Co. Kg | Novel, highly active pyrazolo-piperidine substituted indole-2-carboxamides active against the hepatitis B virus (HBV) |
US20210079015A1 (en) | 2017-11-17 | 2021-03-18 | Novartis Ag | Novel dihydroisoxazole compounds and their use for the treatment of hepatitis b |
US10428070B2 (en) | 2017-12-06 | 2019-10-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
TW201936192A (en) | 2017-12-06 | 2019-09-16 | 美商因那塔製藥公司 | Hepatitis B antiviral agents |
KR102492187B1 (en) | 2017-12-20 | 2023-01-27 | 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이. | 3'3' cyclic dinucleotides with phosphonate linkages that activate STING adapter proteins |
JP2021507906A (en) | 2017-12-20 | 2021-02-25 | ノバルティス アーゲー | Fusion tricyclic pyrazolo-dihydropyrazinyl-pyridone compound as an antiviral agent |
WO2019123339A1 (en) | 2017-12-20 | 2019-06-27 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3' cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
CN111511747A (en) * | 2017-12-21 | 2020-08-07 | 爱尔兰詹森科学公司 | Isoxazole compounds for the treatment of diseases associated with HBV infection |
WO2019129681A1 (en) | 2017-12-28 | 2019-07-04 | F. Hoffmann-La Roche Ag | Dihydropyrimidinylthiazole for the treatment and prophylaxis of hepatitis b virus infection |
WO2019143902A2 (en) | 2018-01-22 | 2019-07-25 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
KR102445054B1 (en) | 2018-02-13 | 2022-09-22 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitors |
ES2962605T3 (en) | 2018-02-26 | 2024-03-20 | Gilead Sciences Inc | Substituted pyrrolizine compounds as inhibitors of HBV replication |
CN111801331A (en) | 2018-02-28 | 2020-10-20 | 诺华股份有限公司 | Indole-2-carbonyl compounds and their use for the treatment of hepatitis b |
JP2021515769A (en) | 2018-03-14 | 2021-06-24 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | Capsid aggregation regulator dosing regimen |
WO2019191166A1 (en) | 2018-03-29 | 2019-10-03 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
WO2019195181A1 (en) | 2018-04-05 | 2019-10-10 | Gilead Sciences, Inc. | Antibodies and fragments thereof that bind hepatitis b virus protein x |
TWI818007B (en) | 2018-04-06 | 2023-10-11 | 捷克科學院有機化學與生物化學研究所 | 2'3'-cyclic dinucleotides |
TW202005654A (en) | 2018-04-06 | 2020-02-01 | 捷克科學院有機化學與生物化學研究所 | 2'2'-cyclic dinucleotides |
TWI833744B (en) | 2018-04-06 | 2024-03-01 | 捷克科學院有機化學與生物化學研究所 | 3'3'-cyclic dinucleotides |
TW201945388A (en) | 2018-04-12 | 2019-12-01 | 美商精密生物科學公司 | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis B virus genome |
EP3781556A1 (en) | 2018-04-19 | 2021-02-24 | Gilead Sciences, Inc. | Pd-1/pd-l1 inhibitors |
WO2019211799A1 (en) | 2018-05-03 | 2019-11-07 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide |
SG11202012425QA (en) | 2018-07-13 | 2021-01-28 | Gilead Sciences Inc | Pd-1/pd-l1 inhibitors |
TW202416959A (en) | 2018-07-27 | 2024-05-01 | 加拿大商愛彼特生物製藥公司 | Substituted tetrahydrocyclopenta [c]pyrroles, substituted dihydropyrrolizines, analogues thereof, and methods using same |
WO2020028097A1 (en) | 2018-08-01 | 2020-02-06 | Gilead Sciences, Inc. | Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid |
US11053235B2 (en) | 2018-08-09 | 2021-07-06 | Janssen Sciences Ireland Unlimited Company | Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases |
WO2020061435A1 (en) | 2018-09-21 | 2020-03-26 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
KR102635333B1 (en) | 2018-10-24 | 2024-02-15 | 길리애드 사이언시즈, 인코포레이티드 | PD-1/PD-L1 inhibitors |
FI3873903T3 (en) | 2018-10-31 | 2024-03-26 | Gilead Sciences Inc | Substituted 6-azabenzimidazole compounds as hpk1 inhibitors |
EP3873608A1 (en) | 2018-10-31 | 2021-09-08 | Gilead Sciences, Inc. | Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity |
EP3873488A4 (en) | 2018-10-31 | 2022-08-03 | The University of Sydney | Compositions and methods for treating viral infections |
TW202031666A (en) | 2018-11-02 | 2020-09-01 | 德商艾庫瑞斯公司 | Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv) |
AR116948A1 (en) | 2018-11-02 | 2021-06-30 | Aicuris Gmbh & Co Kg | DERIVATIVES OF UREA 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PYRAZINES ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV) |
AR117189A1 (en) | 2018-11-02 | 2021-07-21 | Aicuris Gmbh & Co Kg | DERIVATIVES OF 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PIRAZIN INDOL-2-CARBOXAMIDAS ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV) |
AR116947A1 (en) | 2018-11-02 | 2021-06-30 | Aicuris Gmbh & Co Kg | DERIVATIVES OF UREA 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PIRAZINAS-INDOL-2-CARBOXAMIDAS ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV) |
UY38437A (en) | 2018-11-02 | 2020-05-29 | Aicuris Gmbh & Co Kg | NEW UREA 6,7-DIHIDRO-4H-PIRAZOLO [1,5-A] PYRAZINES ACTIVE AGAINST THE HEPATITIS B VIRUS (HBV) |
UY38439A (en) | 2018-11-02 | 2020-05-29 | Aicuris Gmbh & Co Kg | NOVELTY UREA 6,7-DIHYDRO-4H-PYRAZOLE [4,3-C] PYRIDINES ACTIVE AGAINST THE VIRUS OF HEPATITIS B (HBV) |
MX2021005850A (en) | 2018-11-21 | 2021-10-13 | Enanta Pharm Inc | Functionalized heterocycles as antiviral agents. |
TWI827760B (en) | 2018-12-12 | 2024-01-01 | 加拿大商愛彼特生物製藥公司 | Substituted arylmethylureas and heteroarylmethylureas, analogues thereof, and methods using same |
KR20210106421A (en) | 2018-12-20 | 2021-08-30 | 얀센 파마슈티카 엔.브이. | Heteroaryldihydropyrimidine derivatives and methods of treatment of hepatitis B infection |
TW202035412A (en) * | 2018-12-20 | 2020-10-01 | 比利時商健生藥品公司 | Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis b infections |
WO2020135439A1 (en) * | 2018-12-25 | 2020-07-02 | 广东东阳光药业有限公司 | Deuterated dihydropyrimidine compound and use thereof as drug |
MA55020A (en) | 2019-02-22 | 2021-12-29 | Janssen Sciences Ireland Unlimited Co | AMIDE DERIVATIVES USEFUL IN THE TREATMENT OF HEPATITIS B VIRUS INFECTION OR DISEASES INDUCED BY HEPATITIS B VIRUS |
KR20210137518A (en) | 2019-03-07 | 2021-11-17 | 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이. | 3'3'-cyclic dinucleotides and prodrugs thereof |
EP3935065A1 (en) | 2019-03-07 | 2022-01-12 | Institute of Organic Chemistry and Biochemistry ASCR, V.V.I. | 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator |
AU2020231201A1 (en) | 2019-03-07 | 2021-08-26 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2'3'-cyclic dinucleotides and prodrugs thereof |
AU2020249331A1 (en) * | 2019-03-25 | 2021-09-23 | F. Hoffmann-La Roche Ag | Solid forms of a compound of HBV core protein allosteric modifier |
CN111825676B (en) * | 2019-04-15 | 2023-10-17 | 广东东阳光药业股份有限公司 | Dihydropyrimidine compounds and application thereof in medicines |
TW202104210A (en) | 2019-04-17 | 2021-02-01 | 美商基利科學股份有限公司 | Hiv protease inhibitors |
TWI751517B (en) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
TWI751516B (en) | 2019-04-17 | 2022-01-01 | 美商基利科學股份有限公司 | Solid forms of a toll-like receptor modulator |
MX2021013086A (en) | 2019-04-30 | 2021-11-17 | Aicuris Gmbh & Co Kg | Novel phenyl and pyridyl ureas active against the hepatitis b virus (hbv). |
WO2020221826A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel indole-2-carboxamides active against the hepatitis b virus (hbv) |
US20220194951A1 (en) * | 2019-04-30 | 2022-06-23 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compound and application thereof as drug |
JP2022533008A (en) | 2019-04-30 | 2022-07-21 | アイクリス ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | A novel oxalyl piperazine that is active against hepatitis B virus (HBV) |
US20220227789A1 (en) | 2019-04-30 | 2022-07-21 | Aicuris Gmbh & Co. Kg | Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv) |
JP2022532526A (en) | 2019-05-06 | 2022-07-15 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | Amide derivatives useful in the treatment of HBV infections or HBV-induced diseases |
CN113825758B (en) * | 2019-05-14 | 2023-08-01 | 正大天晴药业集团股份有限公司 | Crystal forms of anti-HBV tetrahydroisoxazolo [4,3-c ] pyridines |
EP3972695A1 (en) | 2019-05-23 | 2022-03-30 | Gilead Sciences, Inc. | Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors |
WO2020247444A1 (en) | 2019-06-03 | 2020-12-10 | Enanta Pharmaceuticals, Inc, | Hepatitis b antiviral agents |
US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
US11472808B2 (en) | 2019-06-04 | 2022-10-18 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents |
WO2020245246A1 (en) | 2019-06-06 | 2020-12-10 | F. Hoffmann-La Roche Ag | Alternative process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1h-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid |
WO2020255017A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators |
WO2020255016A1 (en) | 2019-06-18 | 2020-12-24 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators |
PE20220231A1 (en) | 2019-06-25 | 2022-02-07 | Gilead Sciences Inc | FLT3L-FC FUSION PROTEINS AND METHODS OF USE |
US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
US20220257619A1 (en) | 2019-07-18 | 2022-08-18 | Gilead Sciences, Inc. | Long-acting formulations of tenofovir alafenamide |
EP4003355A4 (en) * | 2019-07-31 | 2023-07-26 | Janssen Sciences Ireland Unlimited Company | Dihydropyrimidine derivatives and uses thereof in the treatment of hbv infection or of hbv-induced diseases |
JP2022543010A (en) * | 2019-07-31 | 2022-10-07 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | Dihydropyrimidine derivatives and their use in the treatment of HBV infection or HBV-induced disease |
WO2021034804A1 (en) | 2019-08-19 | 2021-02-25 | Gilead Sciences, Inc. | Pharmaceutical formulations of tenofovir alafenamide |
WO2021055425A2 (en) | 2019-09-17 | 2021-03-25 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
US20220370447A1 (en) | 2019-09-20 | 2022-11-24 | Hoffmann-La Roche Inc. | Method of treating hbv infection using a core protein allosteric modulator |
IL290999B1 (en) | 2019-09-30 | 2024-10-01 | Gilead Sciences Inc | Hbv vaccines and methods treating hbv |
WO2021078221A1 (en) * | 2019-10-24 | 2021-04-29 | 广东东阳光药业有限公司 | Dihydropyrimidine compound and use thereof in drug |
US20230031465A1 (en) | 2019-12-06 | 2023-02-02 | Precision Biosciences, Inc. | Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome |
AU2020404317A1 (en) * | 2019-12-20 | 2022-08-11 | Janssen Pharmaceutica Nv | Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections |
AU2020415322A1 (en) | 2019-12-24 | 2022-06-16 | F. Hoffmann-La Roche Ag | Pharmaceutical combination of antiviral agents targeting HBV and/or an immune modulator for treatment of HBV |
AU2020415307A1 (en) | 2019-12-24 | 2022-06-09 | F. Hoffmann-La Roche Ag | Method of treating virus infection using a TLR7 agonist |
TW202137987A (en) | 2019-12-24 | 2021-10-16 | 瑞士商赫孚孟拉羅股份公司 | Pharmaceutical combination of a therapeutic oligonucleotide targeting hbv and a tlr7 agonist for treatment of hbv |
AU2020412875A1 (en) | 2019-12-24 | 2022-06-23 | Carna Biosciences, Inc. | Diacylglycerol kinase modulating compounds |
AU2021214911A1 (en) | 2020-01-27 | 2022-07-21 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
WO2021183750A2 (en) | 2020-03-12 | 2021-09-16 | Gilead Sciences, Inc. | Methods of preparing 1'-cyano nucleosides |
WO2021188414A1 (en) | 2020-03-16 | 2021-09-23 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
AR121620A1 (en) | 2020-03-20 | 2022-06-22 | Gilead Sciences Inc | 4-C-SUBSTITUTED-2-HALO-2-DEOXIADENOSINE NUCLEOSIDE PRODRUGS AND METHODS OF PREPARATION AND USE THEREOF |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
JP2023523961A (en) | 2020-04-28 | 2023-06-08 | エフ. ホフマン-ラ ロシュ アーゲー | Method for the preparation of chiral piperazine-2-carboxylic acids |
CA3179226A1 (en) | 2020-05-29 | 2021-12-02 | Tomas Cihlar | Remdesivir treatment methods |
IL299202A (en) | 2020-06-24 | 2023-02-01 | Gilead Sciences Inc | 1'-cyano nucleoside analogs and uses thereof |
US20240317735A1 (en) | 2020-07-14 | 2024-09-26 | Hoffmann-La Roche Inc. | Hydroisoquinoline or hydronaphthyridine compounds for the treatment of autoimmune disease |
JP2023536999A (en) | 2020-08-05 | 2023-08-30 | エフ. ホフマン-ラ ロシュ アーゲー | Oligonucleotide treatment of hepatitis B patients |
AU2021320236B2 (en) | 2020-08-07 | 2024-10-03 | Gilead Sciences, Inc. | Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use |
BR112023002951A2 (en) | 2020-08-24 | 2023-03-21 | Gilead Sciences Inc | PHOSPHOLIPID COMPOUNDS AND USES THEREOF |
AU2021331214B2 (en) | 2020-08-27 | 2024-01-04 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
CN111892544A (en) * | 2020-08-31 | 2020-11-06 | 南通大学 | 3- (aminomethyl) -4- (4-fluorophenyl) piperazine-1-carboxylic acid tert-butyl ester and synthesis method thereof |
WO2022052923A1 (en) * | 2020-09-08 | 2022-03-17 | 和博医药有限公司 | Dihydropyrimidine compound and application thereof |
WO2022078479A1 (en) * | 2020-10-16 | 2022-04-21 | Janssen Pharmaceuticals, Inc. | Combination therapy for treating hepatitis b virus infection |
TW202344257A (en) | 2020-10-16 | 2023-11-16 | 美商基利科學股份有限公司 | Phospholipid compounds and uses thereof |
TW202406932A (en) | 2020-10-22 | 2024-02-16 | 美商基利科學股份有限公司 | Interleukin-2-fc fusion proteins and methods of use |
JP2023551048A (en) * | 2020-11-30 | 2023-12-06 | サンシャイン・レイク・ファーマ・カンパニー・リミテッド | Salts, complexes of dihydropyrimidine derivatives and their use in medicine |
CN114621219A (en) * | 2020-12-09 | 2022-06-14 | 上海维申医药有限公司 | Dihydropyrimidine compound, and preparation method and application thereof |
WO2022166923A1 (en) * | 2021-02-05 | 2022-08-11 | 和博医药有限公司 | Phenyldihydropyrimidine compound and use thereof |
CN114853761A (en) * | 2021-02-05 | 2022-08-05 | 刘沛 | Bifunctional derivative containing dihydropyrimidine and application thereof |
CN115210237B (en) * | 2021-02-09 | 2023-11-14 | 上海维申医药有限公司 | Dihydropyrimidine compound, preparation method and application thereof |
AU2022274607A1 (en) | 2021-05-13 | 2023-11-16 | Gilead Sciences, Inc. | COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS |
US20230000873A1 (en) | 2021-05-26 | 2023-01-05 | Gilead Sciences, Inc. | Phospholipid formulations of 1'-cyano substituted carba-nucleoside analogs |
KR20240023628A (en) | 2021-06-23 | 2024-02-22 | 길리애드 사이언시즈, 인코포레이티드 | Diacylglycerol Kinase Modulating Compounds |
MX2023014762A (en) | 2021-06-23 | 2024-01-15 | Gilead Sciences Inc | Diacylglyercol kinase modulating compounds. |
EP4359413A1 (en) | 2021-06-23 | 2024-05-01 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
EP4359415A1 (en) | 2021-06-23 | 2024-05-01 | Gilead Sciences, Inc. | Diacylglyercol kinase modulating compounds |
AU2022328698A1 (en) | 2021-08-18 | 2024-02-01 | Gilead Sciences, Inc. | Phospholipid compounds and methods of making and using the same |
CN114702498B (en) * | 2021-12-23 | 2022-12-16 | 华南理工大学 | Acid addition salts of dihydropyrimidine derivatives and their use in medicine |
CN114702497B (en) * | 2021-12-23 | 2023-03-21 | 华南理工大学 | Crystal form of dihydropyrimidine derivative, preparation method thereof and application thereof in medicines |
EP4320128A1 (en) | 2022-03-02 | 2024-02-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
KR20240154646A (en) | 2022-03-02 | 2024-10-25 | 길리애드 사이언시즈, 인코포레이티드 | Compounds and methods for treating viral infections |
CN118843629A (en) | 2022-03-03 | 2024-10-25 | 吉利德科学公司 | Antiviral compounds and methods of making and using the same |
CN118900839A (en) | 2022-03-03 | 2024-11-05 | 吉利德科学公司 | Antiviral compounds and methods of making and using the same |
WO2023239665A1 (en) | 2022-06-06 | 2023-12-14 | Gilead Sciences, Inc. | Methods for treatment of viral infections including sars-cov-2 |
US20240051962A1 (en) | 2022-06-29 | 2024-02-15 | Gilead Sciences, Inc. | Solid forms of a nucleoside analogue and uses thereof |
WO2024006461A1 (en) | 2022-06-30 | 2024-01-04 | Gilead Sciences, Inc. | Solid forms of a nucleoside analogue and uses thereof |
US20240309028A1 (en) | 2023-02-16 | 2024-09-19 | Gilead Sciences, Inc. | Phospholipid compounds and methods of making and using the same |
WO2024218026A1 (en) | 2023-04-17 | 2024-10-24 | F. Hoffmann-La Roche Ag | Process for the preparation of 4-hydroxy-4,5-dihydrothiazole-2-carbonitrile and derivatives thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014029193A1 (en) | 2012-08-24 | 2014-02-27 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10012549A1 (en) | 2000-03-15 | 2001-09-20 | Bayer Ag | New heterocyclic-substituted dihydropyrimidine derivatives useful for treatment of viral infections, especially hepatitis B infections |
DE10012824A1 (en) | 2000-03-16 | 2001-09-20 | Bayer Ag | New 6-hydroxyhydrocarbyl or 6-thiohydrocarbyl-dihydropyrimidine-5-carboxylic acid derivatives, useful for the treatment of viral infections, especially hepatitis B infections |
DE10013126A1 (en) * | 2000-03-17 | 2001-09-20 | Bayer Ag | New 6-aminoalkyl-dihydropyrimidine-5-carboxylate ester derivatives, useful as antiviral agents having strong activity against hepatitis B virus and low cytotoxicity |
WO2005085462A1 (en) | 2004-02-27 | 2005-09-15 | Dsm Ip Assets B.V. | Enzymatic preparation of an enantiomerically enriched beta-2-amino acids |
WO2006033995A2 (en) | 2004-09-16 | 2006-03-30 | Valeant Research And Development | Thiazolidin-4-ones having anti-hepatitis b activity |
US7629339B2 (en) | 2005-09-22 | 2009-12-08 | The Scripps Research Institute | Alkoxy indolinone based protein kinase inhibitors |
GB0701366D0 (en) | 2007-01-24 | 2007-03-07 | Glaxo Group Ltd | Novel pharmaceutical compositions |
WO2009067547A1 (en) | 2007-11-19 | 2009-05-28 | Takeda Pharmaceutical Company Limited | Polo-like kinase inhibitors |
PL2098526T3 (en) | 2008-02-22 | 2014-06-30 | Neurotune Ag | Nitrogen-containing bicyclic compounds active on chronic pain conditions |
US8470823B2 (en) | 2008-08-29 | 2013-06-25 | Instituto Di Ricerche Di Biologia Molecolare P. Angeletti S.R.L. | Saturated bicyclic heterocyclic derivatives as SMO antagonists |
WO2010069147A1 (en) | 2008-12-17 | 2010-06-24 | 张中能 | Dihydropyrimidine derivatives, compositions thereof and their use |
CN102372706A (en) | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | Phthalazinone derivative, its preparation method and application in medicament |
TW201512193A (en) * | 2013-05-17 | 2015-04-01 | Hoffmann La Roche | Novel 6-bridged heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection |
CN104650069B (en) * | 2013-11-19 | 2019-04-19 | 广东东阳光药业有限公司 | 4- methyl Dihydropyrimidines and its application in drug |
CR20160337A (en) * | 2014-03-07 | 2016-09-20 | Hoffmann La Roche | NEW HETEROARILDIHYDROPIRIMIDINES 6-FUSIONATED FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION |
ES2798598T3 (en) * | 2015-03-16 | 2020-12-11 | Hoffmann La Roche | Combination therapy with a TLR7 agonist and an HBV capsid assembly inhibitor |
WO2017076791A1 (en) * | 2015-11-03 | 2017-05-11 | F. Hoffmann-La Roche Ag | Combination therapy of an hbv capsid assembly inhibitor and an interferon |
AR107633A1 (en) * | 2016-02-19 | 2018-05-16 | Hoffmann La Roche | PROCEDURE FOR THE PREPARATION OF ACID 4-PHENYL-5-ALCOXICARBONIL-2-TIAZOL-2-IL-1,4-DIHYDROPIRIMIDIN-6-IL- [METHYL] -3-OXO-5,6,8,8A-TETRAHIDRO- 1H-IMIDAZO [1,5A] PIRAZIN-2-IL-CARBOXYL |
CN109689059A (en) * | 2016-08-24 | 2019-04-26 | 豪夫迈·罗氏有限公司 | The combination treatment of HBV Mouth Disease Virus Proteins inhibitor and nucleosides or nucleotide analog |
KR102497701B1 (en) * | 2016-09-13 | 2023-02-09 | 에프. 호프만-라 로슈 아게 | Combination therapy of a TLR7 agonist and an HBV capsid assembly inhibitor |
AU2020249331A1 (en) * | 2019-03-25 | 2021-09-23 | F. Hoffmann-La Roche Ag | Solid forms of a compound of HBV core protein allosteric modifier |
US20220370447A1 (en) * | 2019-09-20 | 2022-11-24 | Hoffmann-La Roche Inc. | Method of treating hbv infection using a core protein allosteric modulator |
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